================================================================================ Notes on the effects and pharmacology of 3-trifluoromethylphenylpiperazine (TFMPP) and m-Chlorophenylpiperazine (mCPP) ================================================================================ Subject: TFMPP 4 sale from C.R.S.B. vs. MDMA (my personal experiences) Date: Fri, 12 Sep 1997 11:05:01 -0700 From: Tom Kasper TFMPP (3-Trifluoromethylphenylpiperazine) is available from Chemical Resale of Santa Barbara. Details of the purchase of this legal research chemical can be found on the C.R.S.B. homepage at: http://www.sb.net/wirehead Well. My my my my. I am a clumsy chemist... There I was in my lab weighing out 3-Trifluoromethylphenypiperazine HCl into 5 gram cobalt blue glass vials while enjoying my lunch of Kentucky Fried... Now I know better than to be wedgeing on the grindage next to open bottles of chemicals, but, that chicken tasted soooo good that I just couldn't put it down... I guess I must have accidentally spilled about 100 mg. of TFMPP on my chicken! Me and my poor lab techniques! I didn't even notice my spill! Of course, when i bit down on that chicken leg, I tasted the bitter taste, but too late. I had already swallowed... This was tuesday afternoon at about 5:00 pm, and I was scheduled to go to the Carlos Santana concert at the Santa Barbara County Bowl at 6:30 pm. What to do, what to do? Well, I couldn't dissapoint my beautiful date... I decided not to say anything. I stopped wedgeing on the chicken and left it out on the workbench (a mistake). When my beautiful date arrived, she saw the chicken and decided to have a bite. She too accidentally ingested a little which must have accidentally spilled on another piece of chicken. Oh well... We arrived at the S.B.C.B. for the concert feeling no effect from the ingestion at about 6:30 pm. By the time Santana started playing however, we were feeling the effect of the accidental ingestion of chemical TFMPP... In my estimation, it was similar to, but MORE euphoriant than MDMA which I had accidentally ingested some years back, when it was still legal. The toxic symptoms of ingestion included: 1) Increased socialibility 2) Increased desire to touch and love 3) Enhanced tactile sensations (it felt good to touch things) 4) A feeling of "oneness" with the crowd, and with my date 5) A desire to be very close and to share love with my date Now if you have never seen a Santana show, it is very 60s. "Peace, light, joy, love... You must spread these things" etc. From our perfect seats in the center of the hand carved rock bowl, situated outdoors amid beautiful trees and rolling hills, the experience was, on a scale from one to 10, a 10! I am writing this for education purposes, so that YOU can avoid accidental toxic effects from this chemical... Now please bear in mind that the government of the United States of America has legislated morality such that I am obligated to remind you that the 5 toxic effects of accidental ingestion of TFMPP listed above are, per the U.S. govt. "TOXIC" effects. I must also remind you that my sloppy lab technique is, in no way acceptable, and that I will be certain never to purposefully ingest any chemical ever unless it is prescribed by a bona-fied doctor who charges at least $50.00 per visit and made by a huge corporate drug manufacturer with grossly inflated prices and Calvinist policies. Anything else might cause some special elite FBI group to userp the laws of this great country and act as judge, jury and god and try to execute me on some airplane someplace... Sorry to shout, but... NO CHEMICAL SOLD BY CHEMICAL RESALE OF SANTA BARBARA IS FOR HUMAN CONSUMPTION, EVER, UNDER ANY CIRCUMSTANCES. FURTHER, NO CHEMICAL SOLD BY CHEMICAL RESALE OF SANTA BARBARA IS TO BE USED FOR OR IN FOOD, OR FOR DRUG OR MEDICINAL USE. FINALLY, NO CHEMICAL SOLD BY CHEMICAL RESALE OF SANTA BARBARA IS FOR USE IN EXPLOSIVES, PESTICIDES OR ANY OTHER ILLEGAL USE. SAFE, LEGAL USE OF CHEMICALS SOLD BY CHEMICAL RESALE OF SANTA BARBARA SHALL BE SOLELY THE RESPONSIBILITY OF THE PURCHASER AND END USER. READ THE M.S.D.S.s (MATERIAL SAFETY DATA SHEET) PRIOR TO USE! Thank you for sharing your bandwidth, a.d.c./r.d.c.! Sincerely, Thomas C. Kasper, owner, Chemical Resale of Santa Barbara Investing in America! http://www.sb.net/wirehead ================================================================================ Subject: 1-(3-Chlorophenyl)piperazine sales & info. Author: wirehead@sb.net Date: 1997/11/12 Forums: alt.drugs.chemistry, rec.drugs.chemistry Well. Me and my poor lab technique! Whats a chemist to do? You see I was measuring out 5 gram bottles of the latest addition to the Chemical Resale of Santa Barbara catalog, 3-chlorophenylpiperazine. The repetitive task set my mind to thinking of the Rolling Stones concert that I would attend that evening, and somehow I accidentally spilled two 30 mg. portions of 3-CPP on two tacos that were laying beside the weigh station. Silly me! Well I ate one of the tacos. At just 30 mg., I did not taste the spilled chemical and continued with my task. This was about 5:00 pm. My very beautiful date arrived at about 5:15 and feeling hungry ate the other tainted taco. My My My My! The limo arrived to take us to Dodger Stadium at about 6:00. At this point I realized that I must have accidentally ingested some 3-CPP. I informed my beautiful date of the situation and we decided to make notes about the experience. By comparison, this chemical was not nearly as hallucinogenic as TFMPP, but it had more MDMA like body feeling. There was definite mood elevation after some slight nausea and body flushing that was similar to a "niacin flush". After that, smooth sailing! The chemical experience added to the concert, though a night club would have been a better choice, had the ingestion been conscious. Oh well. For researchers searching for legal substitutes for MDMA to use use on their laboratory primates, I think this chemical will be useful. 3-CPP (3-cholorphenylpiperazine) is available from Chemical Resale of Santa Barbara http://www.sb.net./wirehead for $97.00 for 5 grams. Happy trails, Tom Kasper, owner, Chemical Resale of Santa Barbara http://www.sb.net/wirehead ================================================================================ Subject: Toxicity of MDMA vs. 3-Trifluoromethylphenylpiperazine Author: Tom Kasper Date: 1997/08/08 Forums: alt.drugs.chemistry, rec.drugs.chemistry Research chemicals can be truly dangerous! Accidental ingestion of even small amounts can produce unwanted toxic symptoms. The toxic symptoms of MDMA are reported to be _very_ similar to 1-(3-Trifluoromethylphenyl)piperazine monohydrochloride The amount of MDMA necessary to cause toxic symptoms is almost 200mg, I believe. The amount of 1-(3-Trifluoromethylphenyl)piperazine monohydrochloride is less than 30mg! My point? Please be careful. Toxic symptoms include euphoria, lowering of inhibitions, feelings of empathy, elevated pulse and systolic etc. MDMA, like 1-(3-Trifluoromethylphenyl)piperazine monohydrochloride is a chemical which should not be consumed by humans. Chemical Resale of Santa Barbara, your source for rare organics reminds you that none of our chemicals is sold for food, drug or medicinal use, neither are they sold for use in insecticides or explosives. Most of all, no C.R.S.B. chemical, even pharmaceutically pure chemicals is for human consumption! 1-(3-Trifluoromethylphenyl)piperazine monohydrochloride, 98%, 5 grams............$99.99 This chemical is available for immediate delivery when purchased by credit card via our fax line (805)967-8017 and on-line order form http://www.sb.net/wirehead Thank you for sharing your bandwidth! Sincerely, Tom Kasper, owner, Chemical Resale of Santa Barbara "Dedicated to serving the needs of net scientists worldwide" ================================================================================ Substance: TMFPP Dosage: about 100mg Duration: 2-3 hours plus tail Around 12:30 on a nice day I ( a purely fictional "I" ) decided to try this substance of which I could find exactly two quotations on all of the WWW - a little snippet in Shulgin's PiHKAL (in the section on PEA) and one, single, measly trip-report... So I dropped some of it onto a sugar-cube and ingested it. It is liquid at room-temperature, and at least with my eye-dropper, one drop came out to be between 20 and 25mg -- four drops made 87mg and with a little nudging I managed to get a half-drop onto the cube for a total of 102mg (yes, my scale is that good). This was ingested around 12:45. I made the mistake of taking the "sublingual"-stance too literally and held the cube in my mouth for a minute or two -- for twenty minutes or so afterward my mouth was essentially numb. The substance seems highly caustic and swallowing it in a gel-cap with a glass of water probably would've been a cleverer way of ingestion. Alert at 30min, peak after about an hour. Lasts for two or three hours, then decline. The general impression was that of a mild, pleasant, mellow trippyness. Thoughts flowing freely, but nothing that would "whack me over the head". Full control over everything at all times. OEVs present but borderline (requiring concentration). CEVs mild, pleasant, unspectacular. Call it half a hit of LSD. Contrary to what I had read, there was no jaw-clenching or speedy impression. Actually, a light tremor in my hands was the only peripheral effect I could detect. I didn't even have dilated pupils. In the evening, I went to bed around my usual time (11pm or so) and had no trouble falling asleep -- if anything, I felt exhausted from the activity in my brain. I'd rate this as between "+" and "++" on the Shulgin-scale and maybe "2" on Graeme Carl's scale. Maybe I'm a hardened bastard -- but this whole experience left me utterly unimpressed. I will try this again at higher dosages. ================================================================================ I'll make another comment on the nature of the 4 combo piperazine effects. The drugs seem to have a profound effect on your sleep cycle, especially regarding dreaming. From my experience, and that of others I have conferred with, the piperazines together will dramatically increase the intensity and duration of your dreams the night, not of the day you ingest the chems, but the that of the day after. I've read reports of the drug Serzone having a similar effect on dreaming, and one of it's metabolites is MPP, I believe. I may be mistaken, but I recollect reading the results of a study which showed that MPP would allow some of the subjects to enter into rem sleep at an earlier stage, perhaps level II sleep. Check medline, search under MPP and you should come up with many hits. Anecdotally I'll confirm this. The dreams I have are frighteningly realistic, and I wake up intermittantly, but fall asleep moments later, and the dreams continue rather uninterupted unlike usual. This would suggest that I am dreaming while still in a much lighter sleep. I chop back and forth between being asleep and awake that I can no longer tell which is which. I am exceptionally aware during these dreams, and I often hear myself giving a running commentary on what's happening. Also, the sensations experienced in the dreams are very strong, I can sense touch, smell, and taste to a far greater degree than usual. I still find the whole experience rather confusing, but I imagine if one practiced and learned how to control it that this would be a very attractive quality of the drugs. It somewhat resembles the hallucinations one has on high doses of dissasociates, ie completely immersive and realistic, except that you are much more aware and in control. By the way, I've never experienced anything like this after taking just BZP with TFMPP. I believe that the MPP in probably necessary for this effect. ================================================================================ From: rolf_ernst@buyer-link.com (Rolf Ernst) Subject: TFPP dosage and effects Date: Tue, 23 Sep 1997 00:53:01 GMT I received the following report from an acquaintance of mine who asked me to post the following: A 37 year old 220 pound male accidentally swallowed an approximate 80mg of TFPP. The substance had spilled on a banana which covered the slightly bitter but not repulsive taste. The first effects were felt after 1 hour. After 2 hours the experience had tremendously intensified, leaving the individual in a state of high anxiety and mostly visual hallucinations. The experience was very frightening considering the person had not expected a such strong psychedelic progression. In an attempt the male consumed a third of a bottle of cognac and 150 to 200 mg of Trazodone, a very strong sleep inducing SRI. At the same time he was talked through the reaction by a friend. It took ~ 4 hours before the individual finally fell unconscious. Sleep disturbance lasted for another 3 days. Having consumed the now illegal drug MDMA before the reaction was described as being that of a severed overdose of MDMA. The person in question suggests that a much smaller does of 15-30mg is indicated. It would appear as if the effects while frightening were only of short-term nature and a regular dose would most likely not be felt twelve hours after ingestion. The actual experience can be assumed to be only 4 hours. Regards Rolf Ernst ================================================================================ From: Subject: 1-(3-trifluoromethylphenyl)piperazine monohydrochloride what is the synthesis Date: 26 Sep 1997 04:33:05 GMT cmm@mail.com wrote: : 1-(3-trifluoromethylphenyl)piperazine monohydrochloride what is the : synthesis ? Here's some journal references. Look up the articles and you'll probably find a reference to the synth. If, on the other hand, you are too clueless to know how to use the library to look up journal references and understand organic nomenclature and methods, the synth is probably not much use to you. These refs are at least a starting point for you to do YOUR OWN leg work so quit posting the same damn question over and over again. Glennon, et al., Discriminative stimulus properties of the serotonin agonist 1-(3-trifluoro-methylphenyl)piperazine hydrochloride (TFMPP). Life Sci 35:1475 (1984) Glennon, (1987) Central serotonin receptors as targets for drug research, J. Med Chem. 30:1ff ================================================================================ TFMPP a Pro-anxiety/panicogenic agent! Date: 1997/10/26 Forums: alt.drugs.chemistry I have found this data in the URL http://www.epub.org.br/bjmbr/year1997/v30-3/2800c.htm which contains the article Braz J Med Biol Res, March 1997, Volume 30(3) 289-304 Animal models of anxiety: an ethological perspective R.J. Rodgers, B.-J. Cao, A. Dalvi and A. Holmes Interesting excerpts: For comparative purposes, and particularly in view of similarities in affinity for and action at 5-HT receptor subtypes (5-HT1B and 5-HT2C), parallel studies with the well-known 5-HT anxiogenic agents, mCPP and TFMPP, were also conducted (61). Pro-anxiety/panicogenic agents. Reference has already been made to the anxiogenic-like effects of 5-HT1B/2C agonists (TFMPP, mCPP) (61), ... 61. Rodgers RJ, Cole JC, Cobain MR, Daly P, Doran PJ, Eells JR & Wallis P (1992). Anxiogenic-like effects of fluprazine and eltoprazine in the mouse elevated plus-maze: profile comparisons with 8-OH-DPAT, CGS 12066B, TFMPP and mCPP. Behavioural Pharmacology, 3: 621-634. Is this compatible with the alleged similarity between TFMPP and MDMA? The Poet ================================================================================ BZP & TFMPP euphoriants like MDMA and Meth... Author: Tom Kasper Email: wirehead@sb.net Date: 1997/10/17 Forums: alt.drugs.chemistry, rec.drugs.chemistry Here is a quote from a letter from a resercher who is using TFMPP and BZP HCl in his studies: "Benzylpiperazine Hydrochloride (BZP HCl) simulates methamphetamine use in lab animals. It is a strong anorexic. Anorexic capacity is frequently equated with euphoriant capacity... My observations show this correlation to be true. 3-Trifluofomethylphenylpiperazine Monohydrochloride (TFMPP), mimics MDMA in lab animals. A combination of BZP HCl and TFMPP has been observed to cause activity that is prefered to MDMA in chemical discrimination tests with lab animals. A ratio of 2 parts BZP HCl to 1 part TFMPP was used for these chemical descrimination tests. Larger laboratory primates were given 200 mg. of BZP HCl mixed with 100 mg. of TFMPP. Observed activity appeared to last from 6 to 10 hours. There was an increased sociability observed in all animals given this preparation. Loss of apetite was observed both in the BZP HCl only group and the BZP HCL and TFMPP (2:1) group." TFMPP and BZP HCl are available from Chemical Resale of Santa Barbara at http://www.sb.net/wirehead Thank you for sharing your bandwidth a.d.c./r.d.c. Sincerely, Thomas C. Kasper, owner, Chemical Resale of Santa Barbara Worldwide distribution of the tools of knowledge http://www.sb.net/wirehead ================================================================================ Re: TFMPP & BZP, anecdotals? Author: Mushpot Email: mushp@hotmail.com Date: 1998/10/03 Forums: alt.drugs, alt.drugs.chemistry >Don't remember exactly...I do remember the guidelines for dosage >were taken from Tom Kaspers posts. Perhaps those posts are still >archived on Dejanews. Also this URL may help (it's a bit messy) >http://www.epipe.com/~snabb/News/1-benzylpiperazine.piberaline.fipexide From what I have gathered, a good rough starting dosage for TFMPP and 3-CPP would be around 100mg, with 250 or so being a good hard dose. I would assume that the BZP would be a good addition to this, addinga speedy effect, and making it more suitible for dancing. Maybe 250mg to start, up to maybe 500-1000mg in a night. I think 150-200mg of 3-CPP and 375mg of BZP could probobly masquerade as a good hit of E. ================================================================================ TFMPP Experience Author: Annonymous Email: Annonymous@annon.com Date: 1997/11/30 Forums: alt.drugs.chemistry, rec.drugs.chemistry more headers A few days ago I ingested exactly 100 mgs of TFMPP, hoping to get something out of it. The effects came on in about 30 minutes, but there was no euphoria. Instead, it felt like I took super strong Prozac, it didn't feel bad or good, very neutral. I experienced a slight nervousness of the stomach, but this wasn't unbearable. After about two hours I was feeling pretty disappointed in the TFMPP and I lit up just a small amount of marijuana. Then the strangest thing happened! The stomach nervousness disappeared, and I felt and extremely powerful euphoria, a very clear high, that I have never felt before. It was as if the TFMPP multiplied the effect of the marijuana by 1000. So I think that TFMPP doesn't work alone, but can be used to magnify the effects of other drugs. I wouldn't be suprised if in the future ecstacy pills are cut with TFMPP, or perhaps they are already cut with TFMPP.. Later! ================================================================================ Re: TFMPP & CPP Author: sticker45 Email: sticker45@yahoo.com Date: 1997/11/24 Forums: alt.drugs.chemistry, rec.drugs.chemistry sgg7987@oberlin.edu wrote: > Can anyone give a reasonable comparison between TFMPP & > 3-Chlorophenylpiperazine(CPP)? With or without BZP? Thnx... Well, allow me hypothesise: Both TFMPP and CPP, I believe, are seratonin agonists. CPP's sertonic action is probably more akin to 2-CB and TFMPP's sertonic action is more akain to that of MDMA. I think that ingesting BZP would probably increase the subjective euphoric of both TFMPP and CPP greatly. I have read in some studies of 2-CB that conclude that often, people feel little or no euphoria with 2-CB, but find that 2-CB combined with MDMA greatly enhances the euphoria of the MDMA. So here's my hypothesises: 1) TFMPP or CPP alone don't have much subjective effect. 2) TFMPP combined with BZP would yield a similar subjective experience to MDMA and 3) TFMPP combined with both BZP and CPP would yield a subjective comprable to the subjective experience of MDMA combined with 2-CB. This is indeed a very intresting area of research! ================================================================================ Re: TFMPP Experience Author: Lord Drakon Email: absinthe@sirius.com Date: 1997/12/02 Forums: alt.drugs.chemistry, rec.drugs.chemistry > So I think that TFMPP doesn't work alone, but can be used to magnify the > effects of other drugs. In my primate research, I have noticed a similar effect. The TFMPP acts as a sensory and mood enhancer. Feelings are magnified, whether good or bad. If my animals are being entertained by various pleasant external stimuli (music, lights, sexual touch, etc.), they show signs of euphoria. In the absence of such stimuli, the TFMPP seems to accentuate their boredom and depression. This effect is quite noticeable at dosages as low as 100 micrograms (administered in water under the tongue) in my 75kg primates. I find it surprising that other researchers are reporting dosage levels of a thousand times this much in their experiments. Are the effects nonlinear with respect to dosage? At doses under a milligram, side effects such as muscle tension and "hangovers" are virtually nonexistant. Additionally, administering the medication orally is much easier, as it has only a mild taste in these concentrations. Regards, Lord Drakon (absinthe@sirius.com) ================================================================================ TFMPP, BZP (Benzylpiperazine) --- Experiment #1 --- I recently got ahold of some TFMPP, or 1-(3-trifluoromethylphenyl)piperazine Hydrochloride. Depending on who you ask, TFMPP is supposed to cause effects almost exactly like MDMA. I ate 100 mg in a gelcap. I started to feel trippy effects a little before the one hour point, and effects reached full intensity by around 2.5 hours. The comedown began at the 5 or 6 hour point and I was not completely back to normal until 11 or 12 hours. Quite simply, it was not MDMA. There were some skin sensations that seemed like they could be MDMA-like, but there was none of the incredible emotional release of MDMA. However, there was no question that I was tripping. My thought patterns were trippy, things would breathe slightly if I looked very carefully for it, and music had a trippy edge. A little marijuana seemed to enhance the effects some. My pupils were dilated, my jaw was clenched just a little towards the end of the trip, and I was quite thirsty - at least the physical effects were similar to MDMA. --- Experiment #2 --- 35 mg was taken several days later. This, too, was mixed with marijuana after a while. No quantifiable effects were noticed, so it can be concluded that 100 mg was not any kind of overdose. --- Experiment #3 --- 135 mg was taken after a couple more days. Effects were very similar to 100 mg. Both 100 mg and 135 mg left me with substantial headaches. In both cases, the effects could be categorized as a 1 on the Lycaeum's scale. TFMPP seems to only give a very mild trip, and as far as psychedelics go, it's not really "good", but it is psychedelic. No question about that. --- Experiment #4 --- After more research, I came across some reports that claim that TFMPP needs to be mixed with other piperazines to fully recreate the MDMA effect. I now obtained some benzylpiperazine (BZP) freebase. 50 mg of TFMPP hydrochloride and 90 mg BZP freebase were dissolved in acidic fruit juice. The taste, even in fruit juice, was absolutely vile. The plan was for another evening of marijuana usage with friends, but I held off on the pot until I was able to take note of the effects of the TFMPP/BZP combo. The BZP added a significant speedy effect that was very similar to MDMA. TFMPP's very mild skin sensation was amplified by the BZP, and I felt some degree of pleasure in touching other people. There was still no massive emotional release as with MDMA, nor was there any sort of absolutely clean, pure feeling. But I noticed that the set of effects taken as a whole actually was moving in the general direction of MDMA. The 50/90 combo is a fairly low dose, but I decided to start on the safe side. This combo shows some promise. Marijuana had some effect, but it was subtle and probably only consisted of a "mellowing," like pot has on many other psychedelics. It may have accentuated my ability to take note of what I was feeling. --- Other Experimental Subjects --- Since I now had some idea of the reasonable dose range for these two drugs, I decided to let my friends do some experimenting too. I distributed several 75 mg TFMPP HCl / 150 mg BZP freebase doses to a few people who were experienced with MDMA, and I later talked to them about their experiences. In general, people mentioned the speedy effect and the skin-sensation effects. Most felt that it was lacking the MDMA magic. However, some people pointed out that the effects that were there lasted quite a bit longer than MDMA, and this was generally viewed as a good thing. No one had a chance to explore the emotional disinhibition properties. One friend who often vomits on psychedelics vomited after dosing with the combo. Without exception, the subjects consider the TFMPP/BZP combo to be a worthwhile trip. One friend who is quite experienced with MDMA use and with dancing on MDMA reports that, when she took a 75/150 TFMPP/BZP combo at a concert, she found dancing to be very enjoyable in a way that was essentially the same as MDMA. Another friend later agreed with this assessment. So it would seem that TFMPP/BZP may be particularly useful as an MDMA substitute for raves and similar events, where MDMA's emotional effects take a backseat to the physical joy of dancing. --- Experiment #5 --- After the positive reports I'd heard from my friends, and since I finally had some more free time, I decided to do a 90/180 combo. I had used MDMA two times recently, 7 and 10 days previously, and both were truly outstanding experiences, so my mind had been refreshed about all the relevant characteristics of a good MDMA trip. The combo came on slow. There was no MDMA-like rush. It took about two hours to reach full intensity. There was definitely not the same MDMA emotional characteristics, and I doubt there would be any even at higher doses. So we can rule out the possibility of this combo really mimicing MDMA. However, the overall feel I had was one of extreme pleasantness and contentedness. There were skin sensations that were very similar to MDMA. Not the same - but still, very similar, and enjoyable. Dancing and similar movement was really fun, and I now understand why my friend said she enjoyed dancing on this combo like she does on MDMA. The trip certainly lasts long. The plateau is, maybe, from the 1.5 to 4.5 hour points. The comedown is very slow, subtle, and not at all unenjoyable. At the 10 hour point, I could still clearly feel the drugs, but they were in the background and continued to fade slowly. The trip seemed to come in waves every few minutes, with a new feeling of tingling of the skin, a new feeling of pleasantness, and a new surge of positive trippy energy. BZP on its own behaves very similar to amphetamines, and I definitely felt a more speedy characteristic with this combo than with MDMA. There was significant jaw-clenching and dry mouth. About 10.5 hours after dosing, I fell asleep. My sleep was fitful and uncomfortable. I woke up for dinner, ate, and then fell asleep for an hour again. It took several hours of wakefulness after that final hour-long nap (a total of about 24 hours after dosing) for me to feel completely normal again. I suspect this is because I was already sleepy when I first dosed, and the drugs kept me very awake until they wore off, at which point I crashed hard. My "next day" feelings were probably more negative than they would normally be on the TFMPP/BZP combo. --- Conclusions --- TFMPP on its own is kinda boring. But it may have its uses. If you want a mild trip, with the mental effects but no visuals or sensory disruption, TFMPP will give it to you. It could be used as a way to stay awake; a friend used some this way. However, outside of a couple of narrow uses (and you'd have to try it at least once to see how it could be useful for you), TFMPP on its own seems to be mostly a curiosity, and not too worthy of serious consideration as a psychedelic. However, when mixed with BZP, TFMPP takes on a whole new character. As one of my friends reported earlier, she felt that TFMPP/BZP was very good for dancing, in a way that was quite similar to MDMA, and I agree with her. It does not behave like MDMA, but regardless, the combo is plenty of fun in and of itself; it's definitely now on my list of "preferred psychedelics". It's a wonderful mind-altering but not mind-fucking combo that lends itself very well to social situations, whether that's at a rave, or with just a few friends. It cannot match MDMA's emotional disinhibition qualities, but I can totally understand how people would compare the two. MDMA's core feeling of everything being all right with the world, and its sensation of giving "authenticity" to whatever you might experience on the drug, is there with the combo, and it's awfully enjoyable. I recommend it. I hope to be able to conduct some more experiments with 1-(3-chlorophenyl)- piperazine hydrochloride and 1-(4-methoxyphenyl)piperazine hydrochloride, two more piperazines that can supposedly modulate the TFMPP/BZP combo in all sorts of interesting trippy ways. More reports will be forthcoming once I get a chance to give these a try. by Paradigm Shift (pshift@hotmail.com) ================================================================================ TFMPP: 50 mg, oral: slight effects - mild trippyness: this is not a placebo, but that is pretty much all I know. Out in two or three hours. 100mg oral: Alert after 25 or so minutes, peak from t+1h to t+2.5 hours or so -- then fades out. Trippy mind-set, freely floating thought. Clear presence of CEVs - pretty, yet unspectacular. It is not "good" or "bad": A very un-emotional trip. It's there and that's that. 100mg oral plus 200mg BZP oral: a) We had to deliver our cat to friends who would take care for her over a week we were going to be gone. The substances were ingested before leaving for the metro, and 25 minutes later, sitting in the station I felt quite intoxicated and wondered whether I'd make the train-ride. I peaked pretty much somewhere during the metro-ride. Interestingly my stomach settled quite well - maybe because I was sitting orthogonal to the riding-direction, maybe because I was concentrating on the cat which was frightened in her carrier-box. The prospect of encountering so many people in a very disorganized mind-state would've been frightening without my straight partner around. Later at the friends house, perfectly fine conversations (none of the scatterbrain that acid gives me). Quite social: clear urge to communicate and connect. Quite an insomnia-tail. No appetite all day, and none the next day either. b) At about t+30min I decided to distract myself from my stomach that felt just as upset as last time. Went furniture-shopping. Clear appreciation for the different textures and "feels" of the sofas and the different materials used to make the bureaus we looked at. Again, clearly enhanced openness, urge to communicate and connect, lowered inhibitions to say things that may sound strange. At t+1.5h, went back home to drink some ginger-tea which helped me overcome the remaining twinges of nausea. Spent the rest of the day wandering through the nearby park which helped getting me physically exhausted and thereby alleviated the insomnia-tail a little. Muscle-stiffness in both experiences (a) and (b), felt more strongly the first time when I couldn't move around. This would do well for dancing or similar physical activity. 200mg BZP alone: As one would have expected: the same empathic and social feeling minus the visuals which apparently came more from the TFMPP. Active, communicative, considerably less nausea. Less of a perception that I'm "tripping", which I am very aware of when on TFMPP alone. Tricky, since this seems to alter my behaviour more than TFMPP. ================================================================================ Well, this is what someone could say about 90 TMFPP, 80 BZP, 80 MPP, 35 CPP. Someone got dialated pupils and had visuals like: the carpet moving and swirling, disproportiation when looking at his body, and shroom-like detail of skin and clouds. Someone would attribute these effects to the TMFPP. There were the hot and cold flashes like MDMA (CPP?). And like MDMA it seemed the temperature could be controled by one's mind. Someone could also contol one's mind in physical activities like whether waliking or carrying a bottle of water was an extremely heavy and tiring task or not even noticable(BZP+MPP?). No really speedy effects were noticed. Smoking weed was definately an uplifting experience. Someone would categorize this combo as not like the euphoria of extacy, but more of a light trip. Several of the four people experimenting experienced mild to harsh headaches. This combo was not found to be especially pleasant for social interaction with those not on it. Mild nausea was experienced by someone, but not everyone. This was mainly attributed to the large size of pill and quantity of basic substance in stomach. I tried to be as detailed as possible. Hope this helps. Questions welcome. ================================================================================ I have dreamt that the headache comes from the TFMPP, since any combo containing it (or it alone) caused a severe migraine-like headache. BZP alone does not cause this type of reaction, and I have not dreamt of CPP or MPP alone, so cannot vouch for their effectiveness in the absence of TFMPP. Note that the TFMPP does cause mild LSD-like hallucinogenic effects, but one is better off dreaming with the more traditional fare. The headache is not worth the experience. I'm relieved this was all a dream, because that headache really sucked!! ================================================================================ With reports from several friends, concerning BZP-HCl (100-150 mgs)/ TFMPP-HCl (40-80 mgs) mixes, I have several widely varied reports, some with stomach pains, not attributable to anything else, some with MDMA-like 'pure love' feelings enjoyed while having sex, some with only slight effects, some with very euphoric-sociable-dancing moods, and some with reports of it being better than LSD (coming from a 2-3 time per week user.) BZP is a stimulant, that's for sure, but not quite as 'rewarding' and 'addicting' as amphetamine/methamphetamine, possibly because of it's inablity to be carried around so easily in one's pocket and insufflated whenever one wants. TFMPP is a hallucinogen (expensive, too) that has a peak from 2-4 hours into the trip, with another 2-3 hours to come down, with residual tracer effects lasting beyond 12 hours. ================================================================================ Now I'm a little puzzled: what do you mean "[piperazines are] not in the Merck Index or other medical-type journal"? There seem to be enough literature-refs around -- I have posted a bunch right here at the Lycaeum. I am currently looking into these chemicals myself, but of course they haven't seen decades of abuse and hence there isn't much data on reactions in man. If you're looking for "real scientific information" about, say, BZP, you could access medline somewhere and simply look for 2759-28-6 or 72878-35-4 in the keywords or abstract (these are the CAS-numbers of 1-benzylpiperazine and the HCl salt). You'd get a couple hits and read the abstracts and retrieve the articles and there you'd have "real scientific information". For example: * Glennon, R.A., et al (1989) Binding of arylpiperazines to 5-HT3 serotonin receptors: results of a structure-affinity study. Eur. J. Pharm. 168: 387-392. Which covers a lot of ground and worked quite well for me as an intro to this class of substances. 5-HT3, of course, isn't a particularly "visionary" receptor... As it turns out, the most interesting of the four "commonly abused" piperazines is mCPP (1-(3-Chlorophenyl)piperazine) since it has the highest specificity. Accordingly, there's an abundance of published research about it. For example: * Lucki et al (1989) Effect of 1-(m-chlorophenyl)piperazine and 1-(m-trifluoromethylphenyl)- piperazine on locomotor activity. J. Pharmacol. Exp. Ther. 249: 155. Which, as the title suggests, investigates TFMPP as well - the latter is just of less pharmacological interest. Or how about * Curzon et al (1990) m-CPP: A tool for studying behavioural responses associated with 5-HT1C receptors. TiPS 11: 181. * Baxter et al (1995) 5-HT2 receptor subtypes: A family reunited? TiPS 16: 105. That has a lot research in terms of behaviour rather than pharmacology. Is that what you're looking for? You mentioned metabolizm: * Sugimoto et al (1996) Effects of the 5-HT2C/2B receptor agonist 1-(3-chlorophenyl) piperazine on plasma glucose levels of rats. Eur. J. Pharmacol. 307: 75. Fone et al (1998) Effect of chronic m-CPP on locomotion, hypophagia, plasma corticosterone and 5-HT2C receptor levels in the rat. Br.J.Pharmacol. 123 1707. On a more general level, but dealing a little more with TFMPP again, there's * Schoeffter and Hoyer (1989) Interaction of arylpiperazines with 5-HT1A, 5-HT1B, 5-HT1C and 5-HT1D receptors: do discriminatory 5-HT1B receptor ligands exist? Naunyn-Schmied Arch Pharmacol. 339 675. If your interest is more on the receptor/pharmacology-side (as is mine), you'll find that there are many more piperazines than the commonly touted four. Many of them actually more interesting than those. Like 1-[3-(3,4-Methylenedioxyphenoxy) propyl]-4-phenylpiperazine (BP-554) which is a straight Selective 5-HT1A agonist (which rings the AMT(IT-290)-bell in my head at least). * Glennon et al (1988) Arylpiperazine derivatives as high affinity 5-HT1A serotonin ligands. J.Med.Chem. 31 1968. Or even better: 1-(3-Chlorophenyl)-4-hexylpiperazine which seems to play on the structure of the previous but without the ugly aromatic ring at the end. Or what looks to me to be the most promising, actually: MK 212 (6-Chloro-2-(1-piperazinyl)pyrazine), which is very highly 2C-selective * Conn and Sanders-Bush (1987) Relative efficacies of piperazines at the phosphoinositide hydrolysis-linked serotonergic (5-HT2 and 5-HT1C) receptors. J. Pharmacol. Exp. Ther. 242 552. and seems to be quite psychotropically interesting...: * Lee et al (1992) Effect of the serotonin agonist, MK-212, on body temperature in schizophrenia. Biol. Psychiatry 31 460. ...and there are many more. All it takes is following references in one paper to another one. For example * Hoyer, D. (1988) Functional correlates of serotonin 5-HT1 recognition sites. J. Recept. Res. 8: 59-81 Which opens the door to a world of analogs, homologs, variations - if there's ever a PiHKAL of the piperazine-world, it'll build on this one, I suppose... Some day, I'm going to make a web-page about these interesting little buggers, I promise :) - there's intersting and surprizing pharmacology all around these double-ring strucures... -- GF (randomly throwing out some information) ================================================================================ I understand that TFMPP is a slightly 5-HT[1B] selective partial agonist, with similar potency at 5-HT[1A] and 5-HT[2C] receptors. BZP seems to be a 5HT[3] agonist only. There's something interesting here but I can't put my finger on it... Baxter et al (1995) 5-HT2 receptor subtypes: A family reunited? TiPS 16 105. Glennon R.A., et al (1988) Arylpiperazine derivatives as high affinity 5-HT1A serotonin ligands. J.Med.Chem. 31 1988. Glennon, R.A., et al. (1989) Binding of arylpiperazines to 5-HT3 serotonin receptors: results of a structure-affinity study. Eur. J. Pharm. 168: 387-392. Another interesting reference: Hoyer, D. (1988) Functional correlates of serotonin 5-HT1 recognition sites. J. Recept. Res. 8:59-81 ...goes in the direction I had been thinking of in an earlier post: 4-Phenylpiperidine, 1-(2-Pyrimidinyl)piperazine, 1-naphtyl-Piperazine... Why would these double-ring systems have any effect on 5HT receptors at all? And why selectively? There seems to be a large number of interesting substances out there and it is completely nebulous to me what mechanism they derive their activity from... ================================================================================ What is piperazine monohydrochloride? Does anyone know anything about 1-3(-trifluoromethylphenyl) piperazine monohydrochloride? It is supposedly similar to 3,4-methylenedioxymethamphetamine. Someone posted to Northwest Raves that it was for sale "for research only", unscheduled (i.e. legal), and that 30 mg was equivalent to 200 mg MDMA. Reply from Dave Nichols I've seen no human studies to know its effects. It appears to be a rather nonspecific serotonergic agent. It releases serotonin, and also seems to directly stimulate the 5-HT2A/2C receptors, but supposedly being more selective for the 2C and perhaps only a partial agonist at the 5-HT2A. Its chloro analogue MCPP I know has been given to humans, and the effects, if I remember, were more anxiety-provoking, and were described in one study as "depersonalization." I think TFMPP would clearly have psychoactive effects. The dose range sounds right. It's safety for human use has not been established, but it would likely be safer than MCPP, which has been given to humans, because the trifluoromethyl is quite more inert to metabolism than a chlorine atom. If I personally were going to try the experiment, I'd start at 5 mg, then 10, 18, and 30, in steps, to assure myself that nothing unpleasant might occur at an initial try of 30. My personal thinking is that dopamine release is important to the action of ecstasy. I find no references right at hand to suggest that TFMPP has this effect at all. Thus, a priori, I should suspect that its similarity to ecstasy might be remote. There are many people who lack the discrimination to tell the difference between a Lafite-Rothschild 1932 and a Gallo 1997, or perhaps a better analogy would be that they cannot discern the former from a Budweiser. At first blush, my opinion, purely my opinion, would be that TFMPP would have such a 'resemblance' to ecstasy. If in fact TFMPP is very similar, or extremely similar to ecstsasy, then I would VERY MUCH like to know that from someone who has discriminating tastes. ================================================================================ ::::::::::::::::::AD: Department of Psychiatry, University of Pittsburgh, PA. SO: Brain-Res. 1987 Dec 8; 436(1): 92-102 PY: 1987 LA: ENGLISH CP: NETHERLANDS AB: Fluoxetine and trifluoromethylphenylpiperazine (TFMPP) were studied for their short-term effects on electroencephalographic sleep in male rats. Following single injection, each drug produced a sizeable, dose-related suppression of rapid-eye-movement (REM) sleep that persisted for 4-5 h (fluoxetine, 0.625-5 mg/kg; TFMPP, 0.10-1.25 mg/kg). TFMPP also consistently increased non-REM (NREM) sleep during the second hour after drug injection, though this effect was not dose-related (it was seen at all doses tested). Fluoxetine produced small effects on NREM sleep that varied non-systematically with dose and time after drug injection. TFMPP, but not fluoxetine, also increased at all doses the number of delta waves per minute of NREM sleep in the second hour. A structural analog of TFMPP that is inactive at serotonin (5-HT) receptors [4-(m-trifluoromethylphenyl)piperadine; LY97117] was also tested, and found to be devoid of effects on NREM and REM sleep. Both fluoxetine (a 5-HT reuptake blocker) and TFMPP (a 5-HT agonist) enhance transmission across 5-HT synapses, though by different mechanisms. Because they have the common effect of suppressing REM sleep, and in a dose-related manner, the data support the notion that 5-HT neurons in the brain, when active, can suppress REM sleep. ================================================================================ Subj: Fipexide metabolite Date: 97-09-10 13:26:48 EDT From: Davedude11 Piperonylpiperazine or 1(3,4-methylenedioxyphenyl)piperazine, An active metabolite of the nootropic fipexide. Gentlemen I have been looking for fipexide for about 6 weeks and Lupus recently had told me about this stuff. Fipexide ain't around anymore:(nobody sells it that I can access, anyway) can you direct me or inform me of the effects of this material in comparison, or provide anecdotal information.?? Any comparative analyses such as "Researchers have noted that the ingestion of (X) grams essentially duplicates one standard 600 milligram dose of Fipexide in laboratory settings."??? Thank you for your anticipated response. David ================================================================================ See wirehead is a little crazy, but aint we all? BZP - benzylpiperazine HCl makes 3-CPP -3-chlorophenylpiperazine and 3-trifluoromethylphenylpiperazine and 4-methoxypiperazine work real good. The 3-trifluoro is the visuals. The 3-CPP is the body feelings. The 4-methoxy is the body calming and the BZP makes it all work. Want more visuals? Add 3-Trifluoro. Want more body feelings? add more 3-CPP. I use 1/8 gram of BZP with 1/8 gram of 3-trifluoro and 30mg of 3-CPP and 75mg of 4-methoxy. This is the best! ================================================================================ From: Zaphraud Subject: Re: ME and TFMPP Date: Fri, 10 Oct 1997 18:10:18 -0700 .TFMPP experiences. .I was quite stoked at the prospect of finding a readily accessible chemical .which evidently induced a similar state of Euphoria as that resulting from .MDMA. .My first experience. .I received my shipment from CRSB (in a very timely manner), and quickly cut .out a small portion on my Jimi Hendrix mirror. Didn't weight it but I figured .it in the 20 - 30 Mg range. The burn was much worse then the worst crank I had .ever been unfortunate enough to happen upon. Within moments I began feeling .the effects. Complete euphoria? I think not! In fact, the complete opposite. I .became very anti-social, stopped answering the phone and actually cancelled my .plans to go dancing that evening. I was at a complete loss for what to do with .myself ad either wanted the horrible feelings to end or simply fall asleep. I .crept in to bed and woke up the next morning with no hangover. The whole .experience lasted about 4 hours. ACK! You know, this sounds as though it might be somewhat accurate. Here's some information on mCPP, TFMPP (mTFMPP), and other TFMPP analogs. If anything, the information seems to indicate that on a receptor level it is somewhat similar to LSD, but with a far, far greater potential for side effects (5HT3 is the receptor that would be involved with nausea, I do believe) and much lower potency. Given that LSD is, pharmalogically, just about enough antagonist to totally block its own action (but not quite!), theres a chance that the "ecstasy" being experienced is, in most cases, a result of the mixture of this extremely mild serotonergic with stimulant... in most cases probably phenylpiperazine (which Shulgin, a trusted source, confirms is indeed a stimulant of some nature). Frankly, it seems as though the combination of fenfluramine with a long- lasting dopaminergic stimulant (d-amphetamine?) seems a far safer, better traveled path towards simulating the "ecstasy" experience. I'd like to see some reports on FenDexing, if anyone has any to offer... Abstracts of articles of interest on meta-ChloroPhenylPiperizine. ----------------------------------------------------------------------------- HN--\ _____ _____ _____/ \\ / _ \ / \ / _ \ \\ < (_) >--N NH < (_) >----C NH2 \_____/ \_____/ \_____/ \_____/ / / Cl The mCPP molecule. HO Serotonin (5HT). [Rotationally restricted] [Bent this way] ----------------------------------------------------------------------------- BINDING OF ARYLPIPERAZINES TO 5-HT3 SEROTONIN RECEPTORS: RESULTS OF A STRUCTURE-AFFINITY STUDY. Glennon RA; Ismaiel AE; McCarthy BG; Peroutka SJ Department of Medicinal Chemistry, School of Pharmacy, Medical College of Virginia, Virginia Commonwealth University, Richmond 23298-0581. Eur J Pharmacol 168: 387-92 (1989) Abstract The binding affinities of a series of arylpiperazine derivatives at [3H]quipazine-labeled central 5-HT3 sites were investigated. Features determined to be important for binding include the N4 piperazine nitrogen atom (but not the N1 piperazine nitrogen), and a quinolinyl ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ group. The quinoline nitrogen atom of quipazine also contributes to affinity and its replacement by carbon reduces affinity by 20-fold. The entire quinoline nucleus is not necessary for binding, and certain monocyclic arylpiperazines, particularly those with a chloro group meta to the position of the piperazine ring (e.g. mCPP, MK-212), also bind at 5-HT3, sites; however, the affinities of these agents are at least an order of magnitude less than that of quipazine itself. Taking advantage of the fact that tertiary amines are not well tolerated at 5-HT1B sites, but that N-methyl substituents have little effect on 5-HT3 binding, we designed and synthesized a tertiary amine analog of quipazine, i.e., N-methylquipazine (NMQ). NMQ binds at 5-HT3 sites with an affinity similar to that of quipazine; however, unlike quipazine, NMQ shows very little affinity (IC50 greater than 10,000 nM) for central 5-HT1B sites. ----------------------------------------------------------------------------- M-CHLOROPHENYLPIPERAZINE AND M-TRIFLUOROMETHYLPHENYLPIPERAZINE ARE PARTIAL AGONISTS AT CLONED 5-HT2A RECEPTORS EXPRESSED IN FIBROBLASTS. Grotewiel MS; Chu H; Sanders-Bush E Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee. J Pharmacol Exp Ther 271: 1122-6 (1994) Abstract Serotonin2A (5-HT2A) and 5-HT2C receptors share numerous pharmacological properties. Two compounds thought to discriminate between these two receptor subtypes are m-chlorophenypiperazine (mCPP) and m-trifluoromethylphenylpiperazine (TFMPP). _____ _____ / _ \ / \ < (_) >--N NH \_____/ \_____/ The mTFMPP molecule. / CF3 These two drugs have been classified as antagonists at 5-HT2A receptors but as agonists at 5-HT2C receptors on the basis of phosphoinositide hydrolysis studies in cerebral cortex and choroid plexus, respectively. To determine more fully the properties of mCPP and TFMPP at 5-HT2A receptors, NIH 3T3 fibroblasts transfected with the 5-HT2A receptor complementary DNA (GF6 cells) were used as a model system of receptor function. These cells express approximately 15-fold higher 5-HT2A receptor density than is found in cerebral cortex. In GF6 cells, mCPP and TFMPP dose-dependently stimulated phosphoinositide hydrolysis with maximal effects less than that of 5-HT. This agonist activity was blocked by 5-HT2A receptor antagonists but not by prior treatment with pertussis toxin. Partial inactivation of 5-HT2A receptors with phenoxybenzamine decreased the maximal effects of mCPP and TFMPP but did not eliminate agonist activity. Thus mCPP and TFMPP are partial agonists at 5-HT2A receptors in GF6 cells, and these agonist properties are retained even under conditions where receptor density is comparable to that of cerebral cortex. Although it has not yet been demonstrated that mCPP and TFMPP are agonists at central 5-HT2A receptors, this possibility should be considered when evaluating in vivo effects of these drugs. ----------------------------------------------------------------------------- CALCINEURIN INHIBITS DESENSITIZATION OF CLONED RAT 5-HT1C RECEPTORS. Boddeke HW; Hoffman BJ; Palacios JM; Hoyer D Sandoz Pharma Ltd, Basle, Switzerland. Naunyn Schmiedebergs Arch Pharmacol 348: 221-4 (1993) Abstract Functional responses to stimulation of rat 5-HT1C receptors expressed in A9 cells were studied using whole cell voltage clamp recording technique. Stimulation of 5-HT1C receptors with serotonin (5-HT) evoked calcium-dependent outward currents of 109 pA in cells clamped at -50 mV. Pretreatment with the protein kinase C (PKC) activator phorbol myristic acetate (PMA) reduced the 5-HT-induced current amplitude by 46% of the control value. Inclusion of inositol triphosphate (IP3) in the pipette solution induced an outward current of 84 pA. The IP3-induced response was not affected by 60 min pretreatment with PMA. In the presence of the PKC antagonist calphostin C, 60 min treatment with PMA (10(-6) mol/l) reduced the 5-HT response only by 8%. In cells preincubated with PMA, injection of the calcium/calmodulin dependent serine proteinphosphatase calcineurin gradually increased the 5-HT-induced responses by 34%. In A9 cells which were incubated 24 h with the 5-HT1C receptor agonist meta-chlorophenyl- piperazine hydrochloride (mCPP), 5-HT-induced responses were reduced by 23% of the vehicle pretreated control value. Injection of calcineurin in mCPP treated cells enhanced the 5-HT-induced response by 24%. The results suggest that in A9 cells rat 5-HT1C receptors are desensitized after phosphorylation by PKC. This desensitization can be counteracted by calcineurin-induced dephosphorylation. ----------------------------------------------------------------------------- ACTIVITY OF AROMATIC SUBSTITUTED PHENYLPIPERAZINES LACKING AFFINITY FOR DOPAMINE BINDING SITES IN A PRECLINICAL TEST OF ANTIPSYCHOTIC EFFICACY. Martin GE; Elgin RJ Jr; Mathiasen JR; Davis CB; Kesslick JM; Baldy WJ; Shank RP; DiStefano DL; Fedde CL; Scott MK Department of Biological Research, McNeil Pharmaceutical and Janssen Research Foundation Worldwide, Spring House, Pennsylvania 19477. J Med Chem 32: 1052-6 (1989) Abstract Generally, antipsychotic agents are dopamine receptor blocking agents that also block conditioned avoidance responding (CAR) in the rat. Recently, however, both (Q-methoxyphenyl)piperazine (OMPP, 1h) and (m-chlorophenyl)- piperazine (MCPP, 1o) have been reported to block conditioned avoidance responding in the rat although neither has dopamine receptor blocking properties. The present paper examines the behavioral and biochemical profile of a number of additional substituted phenylpiperazines. None of the phenylpiperazines tested demonstrated high affinity for either dopamine D-1 or D-2 receptor sites, yet many were effective in blocking CAR. The results suggest that the phenylpiperazines may be effective antipsychotic agents without blocking dopamine receptors. Moreover, the active compounds did demonstrate activity in displacing ligand binding to serotonin receptors. Receptor binding profiles were determined for 5-HT-1A and 5-HT-1B binding sites as well as for 5-HT-2 sites. The data from this preclinical test suggest these phenylpiperazines might be effective antipsychotic agents acting via a nondopaminergic mechanism of action. ----------------------------------------------------------------------------- 5-HT1 AND 5-HT2 BINDING CHARACTERISTICS OF SOME QUIPAZINE ANALOGUES. Glennon RA; Slusher RM; Lyon RA; Titeler M; McKenney JD J Med Chem 29: 2375-80 (1986) Abstract Arylpiperazines, such as 1-(3-trifluoromethylphenyl)piperazine (TFMPP) and its chloro analogue mCPP, are 5-HT1 agonists, whereas quipazine, i.e., 2-(1-piperazino)quinoline, appears to be a 5-HT2 agonist. Radioligand binding studies using rat cortical membrane homogenates and drug discrimination studies using rats trained to discriminate a 5-HT1 agonist (i.e., TFMPP) or a 5-HT2 agonist (i.e., 1-(2,5-dimethoxy-4-methylphenyl)- 2-aminopropane (DOM)) from saline reveal that quipazine and its 1-deaza analogue 2-naphthylpiperazine (2-NP) bind at 5-HT1 and 5-HT2 sites but produce stimulus effects similar to those of DOM. A structurally related compound, 1-naphthylpiperazine (1-NP), possesses a high affinity for 5-HT1 (Ki = 5 nM) and 5-HT2 (Ki = 18 nM) sites. 1-NP produces stimulus effects similar to those of TFMPP and is able to antagonize the stimulus effects produced by DOM. The present results suggest that the unsubstituted benzene ring of quipazine, and of its 1-deaza analogue 2-naphthylpiperazine, makes a significant contribution to the binding of these agents to 5-HT2 sites and, more importantly, may account for their 5-HT2 agonist properties. ___ > Linux - the answer to the microsoft problem / _ _ |_ _ _ _| Sysop - The Portal BBS - 805/642-7038 <____(_(|_)| )| `(_((_)(_| jkenner@rain.org | Incoming UCE will be BILLED! ================================================================================ Re: BZP & TFMPP euphoriants like MDMA and Meth... Author: Arno Email: contactable@spamgohome.earthling.net Date: 1997/10/28 Forums: alt.drugs.chemistry >>> In my experience (which I posted previously), BZP is not much >>> of a euphoriant at all. There felt like a serotonin syndrome sort >>> of thing going on accompanied by stimulation. But there was little >>> euphoria. > > IT Aint like real zip. (period)! And I know what I am sending here is also not like the real zip. Theory is always dry, and this is some theory again, but fits in with the header. There are presently and 236 abstracts about research involving TFMPP available on Medline, 6 of them with both keywords, TFMPP _and_ MDMA. Great place to have a look. Many thanks to Samson, for making me aware of it. Here is a brief selection of articles, just to give an idea what to expect there. I am presently quite time-pressed, so I didn't actually select much, no time to go through the contents in detail. Towards the end, there is a very recent article that suggests that laboratory rats can hardly distinguish mdma from fenfluramine. I think in some studies, not all though, that has been similar with TFMPP, the poor little ones couldn't distinguish it well, and that's where the whole myth that it's an MDMA-like drug originates from. However, in combination with an amphetamine-type compound, the similarity will probably go up. But there seem to be differing results in some studies, and the whole picture is a little complicated. Didn't find time to really have a thorough look at it. Also, my interest isn't really that much, to be honest. Anyway, here are the abstracts. -------------------------------------------------------------------------------- Title Use of TFMPP stimulus properties as a model of 5-HT1B receptor activation. Author Schechter MD Address Department of Pharmacology, Northeastern Ohio Universities College of Medicine, Rootstown 44272. Source Pharmacol Biochem Behav, 1988 Sep, 31:1, 53-7 Abstract Recent evidence indicates that when 1-(3-trifluoromethylphenyl)piperazine (TFMPP) is used as a training drug in the drug discrimination paradigm it produces a stimulus effect that is site-selective at the 5-HT1B receptor. The present study sought to employ this procedure in order to assess the similarity of novel agents to TFMPP. First, rats were trained to reliably discriminate between the stimulus properties of intraperitoneally administered 1.0 mg/kg TFMPP and its vehicle. Following the acquisition of this discrimination, administration of various doses of TFMPP produced a typical dose-response relationship with an ED50 of 0.27 mg/kg. Rats were subsequently tested with another 5-HT1B specific agonist 1-(3-chlorophenyl)piperazine (mCPP) and a 5-HT releasing agent norfenfluramine and both produced TFMPP-like discriminative responding in a dose-dependent manner. In contrast, the 5-HT2 agonist 4-iodo-1-(2,5-dimethoxyphenyl)-2-aminopropane (DOI) did not generalize from TFMPP. Other drugs, previously trained in other rats and shown to generalize to TFMPP, viz., ethanol, tetrahydro-beta-carboline (THBC) and 3,4-methylenedioxymethamphetamine (MDMA) did not produce TFMPP-like responding. These results provide further evidence for the 5-HT1B receptor acting as the site for the discriminative effects of TFMPP. In addition, the transfer of discrimination between TFMPP and either ethanol, THBC or MDMA appears to be asymmetrical. Reasons for this one-way generalization are suggested. Language of Publication English Unique Identifier 89297108 -------------------------------------------------------------------------------- Title Mechanistic investigation of the stimulus properties of 1-(3-trifluoromethylphenyl)piperazine. Author Herndon JL; Pierson ME; Glennon RA Address Department of Medical Chemistry, School of Pharmacy, Medical College of Virginia, Virginia Commonwealth University, Richmond 23298. Source Pharmacol Biochem Behav, 1992 Nov, 43:3, 739-48 Abstract Using a standard two-lever operant procedure with rats trained to discriminate 1-(3-trifluoromethylphenyl)piperazine (TFMPP) (0.5 mg/kg) from saline, tests of stimulus antagonism and stimulus generalization were performed to better understand the stimulus properties of this agent. The agents examined for ability to antagonize the TFMPP stimulus were prazosin, quipazine, zacopride, buspirone, 8-hydroxy-2-(di-N-propylamino) tetralin (8-OH-DPAT), 1-(2-methoxyphenol)-4-[4-(2-phthalimido)butyl]-piperazine (NAN-190), haloperidol, and 1-(2-pyrimidinyl)piperazine (1-PP); only buspirone attenuated the response to TF-MPP. In separate experiments, the lowest nondisrupting dose of buspirone (1.2 mg/kg) caused a rightward shift of the TFMPP dose-response curve (TFMPP alone, ED50 = 0.19 mg/kg; TFMPP + buspirone, ED50 = 0.43 mg/kg). In addition, 3-(1,2,5,6-tetrahydropyrid-4-yl)pyrrolo[3,2-b]pyrid-5-on e (CP 93, 129), 7-trifluoromethyl-4-(4-methyl-1-piperazinyl)pyrolo[1,2-a]quinox ali ne (CGS 12066B), 1-(2,5-dimethoxy-4-iodopheny l)-2-aminopropane (DOI), 3-chlorophenylbiguanide (mCPBG), NAN-190, nisoxetine, zacopride, 1-PP, (+)-N-allylnormetazocine ((+)-NANM), and N-methyl-1-(3,4-methylenedioxyphenyl)-2-aminopropane (MDMA) were analyzed in tests of stimulus generalization. The TFMPP stimulus generalized only to CGS 12066B (ED50 = 4.2 mg/kg) and (+)-NANM (ED50 = 8.8 mg/kg). Tests with DOI and MDMA resulted in partial generalization. Up to doses that disrupted behavior, all other agents had little effect on TFMPP-appropriate responding. The results of these and other published studies suggest roles for 5-hydroxytryptamine 1B (5-HT1B), 5-HT1C, and, possibly, sigma-receptors in the mediation of the TFMPP stimulus and indicate a lack of involvement of 5-HT1A, 5-HT2, dopaminergic, and adrenergic mechanisms in this behavior. Language of Publication English Unique Identifier 93079272 -------------------------------------------------------------------------------- Title The quipazine- and TFMPP-increased conditioned avoidance response in rats: role of 5HT1C/5-HT2 receptors. Author Alhaider AA; Ageel AM; Ginawi OT Address Department of Pharmacology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia. Source Neuropharmacology, 1993 Dec, 32:12, 1427-32 Abstract The role of serotonin (5-HT) in the acquisition of the conditioned avoidance response was investigated. The effects of different serotonin agonists and antagonists, administered prior to learning sessions, were studied in groups of naive rats using the two-way shuttle box. Quipazine, an agonist at 5-HT1B/1C/2 receptors, significantly increased avoidance responding in a dose-dependent manner (1.25-10 mg/kg, s.c.). The putative 5-HT1B/1C receptor agonist TFMPP (1-[m-trifluoromethylphenyl] piperazine) at doses of 1.25 and 2.5 mg/kg (s.c.), increased acquisition of conditioned avoidance but showed no significant difference from control at doses of 5 and 10 mg/kg. The 5-HT1A agonist, buspirone, significantly decreased acquisition of conditioned avoidance. Increased acquisition of conditioned avoidance induced by either quipazine or TFMPP was effectively antagonized by the mixed 5-HT 1C/2 receptor antagonists, ketanserin (0.2 and 2 mg/kg, s.c.) and mianserin (1 mg/kg, s.c.). In contrast, spiperone (5-HT1A/2 receptors antagonist: 0.2 mg/kg, s.c.) only inhibited the increased acquisition induced by TFMPP. On the other hand, the 5-HT1A/1B receptors antagonist, pindolol, failed to antagonize the increase in acquisition of conditioned avoidance caused by quipazine or TFMPP. These results suggest that quipazine increases the conditioned avoidance behaviour by an action that might be mediated through stimulation of 5-HT1C receptors. The acquisition of conditioned avoidance induced by TFMPP, which was blocked by ketanserin, mianserin and spiperone but not by pindolol, suggests the involvement of 5-HT1C/2 receptors in the action of TFMPP. Language of Publication English Unique Identifier 94203350 -------------------------------------------------------------------------------- Title Psychopharmacological profile of 1-(m-(trifluoromethyl) phenyl) piperazine (TFMPP). Author Frances H Address INSERM U-302, Faculté de Médecine Pitié Salpêtrière, Paris. Source Pharmacol Biochem Behav, 1988 Sep, 31:1, 37-41 Abstract The effect of TFMPP, an agonist of the 5-HT1b receptors, was studied in mice on several psychopharmacological parameters. In contrast to imipramine-like drugs, TFMPP neither antagonized reserpine-induced hypothermia nor increased yohimbine-induced toxicity. Similarly to imipramine-like drugs, TFMPP antagonized oxotremorine-induced hypothermia and was active in the behavioural despair test. In addition, TFMPP normalized a social behavioural deficit induced by isolation. The effects of TFMPP on oxotremorine-induced hypothermia in the behavioural despair test and in the isolation-induced social behavioural deficit are all antagonized by d-1 propranolol. It is concluded that TFMPP seems to possess psychotropic activity resembling only in part that of imipramine-like drugs and that these actions may be mediated through 5-HT1b receptors. Language of Publication English Unique Identifier 89297106 Title Possible 5-hydroxytryptamine1 (5-HT1) receptor involvement in the stimulus properties of 1-(m-trifluoromethylphenyl)pipe razine (TFMPP). Author Cunningham KA; Appel JB Source J Pharmacol Exp Ther, 1986 May, 237:2, 369-77 Abstract Male rats (N = 24) were trained to discriminate 1-(m-trifluoromethylphenyl)piperazine (TFMPP) (0.8 mg/kg) from saline in a two-lever, drug discrimination situation. 5-Hydroxytryptamine (5-HT) agonists such as fenfluramine (0.8-1.6 mg/kg), m-chlorophenylpiperazine (0.1-1.6 mg/kg) and RU 24969 (0.1-1.6 mg/kg) mimicked TFMPP; 8-hydroxy-2-(di-n-propylamino)tetralin (0.02-0.32 mg/kg) and quipazine (0.2-3.2 mg/kg) elicited saline lever responding; d-lysergic acid diethylamide (0.1-0.16 mg/kg) produced intermediate results. The 5-HT antagonists BC 105 (1.6-12.8 mg/kg), bromolysergic diethylamide (0.8-1.28 mg/kg), ketanserin (0.8-6.4 mg/kg), Ly 53857 (0.2-1.6 mg/kg) and pirenperone (0.08-0.64 mg/kg) failed to attenuate the TFMPP cue; metergoline (0.4-6.4 mg/kg) and spiperone (0.08-1.28 mg/kg) decreased drug lever responding by as much as 60%. These data suggest that 5-HT agonists are not identical and that drug discrimination procedures can differentiate among them. Given that there is strong evidence to support the existence of heterogeneous 5-HT receptors, the present results also suggest that TFMPP acts through mechanism(s) similar to those of the novel 5-HT1 agonists m-chlorophenylpiperazine and RU 24969; these actions can be differentiated from those underlying d-lysergic acid diethylamide, quipazine and 2,5-dimethoxy-4-methylamphetamine, which are attenuated by putative 5-HT2 antagonists. Thus, the authors propose a role for 5-HT1 receptors in mediating the stimulus effects of TFMPP, although further research is necessary to identify functional antagonists of such systems. Language of Publication English Unique Identifier 86199670 -------------------------------------------------------------------------------- Title Effects of repeated administration of the monoamine oxidase inhibitor phenelzine on the discriminability of d-lysergic acid diethylamide (LSD) and 1-(m-trifluoromethylphenyl) piperazine (TFMPP). Author Cunningham KA; Carroll BA; Appel JB Source Psychopharmacology (Berl), 1986, 89:1, 134-5 Abstract Rats trained to discriminate d-lysergic acid diethylamide (LSD; 0.08 mg/kg) or 1-(m-trifluoromethylphenyl) piperazine (TFMPP; 0.8 mg/kg) were treated with the monoamine oxidase inhibitor (MAOI) phenelzine (10 mg/kg/day) for 7 days. After a 24 h "washout" period, they were challenged with the training drug (and dose) or saline, during extinction test sessions. Following 0.08 mg/kg LSD, LSD-trained rats responded primarily on the saline lever (29% drug-appropriate responding) while, after TFMPP (0.8 mg/kg), TFMPP-trained animals responded on the drug lever (75% drug-appropriate responding). These preliminary data suggest that, if serotonin receptors are involved in the behavioral effects of TFMPP, these receptors differ from those involved in the effects of LSD. Language of Publication English Unique Identifier 86287822 -------------------------------------------------------------------------------- Title Exploratory hypoactivity induced by m-trifluoromethylphenylpiperazine (TFMPP) and m-chlorophenylpiperazine (m-CPP). Author K…odzi2ska A; Jaros T; Chojnacka-Wójcik E; Maj J Address Institute of Pharmacology, Polish Academy of Sciences, Kraków. Source J Neural Transm Park Dis Dement Sect, 1989, 1:3, 207-18 Abstract The action of m-trifluoromethylphenylpiperazine (TFMPP) and m-chlorophenylpiperazine (m-CPP), inhibiting the exploratory activity (ambulation and peeping) of the rat was studied in the open field test. The effects of both these drugs were antagonized by mesulergine, metergoline and mianserin, and partly by methysergide. Spiperone showed an antagonistic action in one (mean) dose only. The effects of TFMPP and m-CPP were not antagonized by ipsapirone, gepirone, cyanopindolol, compound 21009, cyproheptadine, ritanserine, ICS 205930, idazoxan or atropine. The lesion produced by p-chloramphetamine attenuated the effects of TFMPP and abolished those of m-CPP. The obtained results permit an assumption that the TFMPP- and m-CPP-induced decrease in the exploratory activity is mediated probably by 5-HT1C receptors. Language of Publication English Unique Identifier 89374735 -------------------------------------------------------------------------------- Title Effect of 1-(m-chlorophenyl)piperazine and 1-(m-trifluoromethylphenyl)piperazine on locomotor activity. Author Lucki I; Ward HR; Frazer A Address Department of Psychiatry, University of Pennsylvania, Philadelphia. Source J Pharmacol Exp Ther, 1989 Apr, 249:1, 155-64 Abstract The piperazine-type 5-hydroxytryptamine (5-HT) agonists 1-(m-trifluoromethylphenyl)piperazine (TFMPP), 1-(m-chlorophenyl)-piperazine (m-CPP), 1-(p-chlorophenyl)piperazine (p-CPP) and MK-212 [6-chloro-2-(1-piperazinyl)pyrazine], produced a dose-dependent suppression of spontaneous ambulatory behavior in rats. Pretreatment with the 5-HT antagonists metergoline, methysergide or mianserin, but not selective 5-HT2 or catecholamine antagonists, blocked the reduction of activity caused by TFMPP suggesting that the stimulation of 5-HT receptors was involved in causing this behavioral effect. Other behavioral signs of 5-HT receptor stimulation, such as the 5-HT behavioral syndrome or head-shaking behavior, were not observed in rats injected with TFMPP, m-CPP or MK-212 except at toxic doses. The ability of piperazine agonists to reduce locomotor activity in rats was altered by long-term changes in 5-HT neurotransmission. The destruction of 5-HT neurons by i.v.t. injection of the neurotoxin 5,7-dihydroxytryptamine potentiated the ability of m-CPP to inhibit ambulatory behavior. On the other hand, elevating 5-HT content by administering the monoamine oxidase inhibitors phenelzine or nialamide for 7 days reduced the ability of m-CPP to suppress locomotor activity. Acute administration of the monoamine oxidase inhibitors, or chronic administration of other antidepressants such as desmethylimipramine or iprindole, failed to alter m-CPPs activity-suppressant effects. These studies suggest that chronic changes in 5-HT neurotransmission produce compensatory changes which alter the behavioral response to these piperazine agonists. Taken together with other evidence that both TFMPP and m-CPP are agonists at 5-HT1B and 5-HT1C receptors, the effects of TFMPP and m-CPP on locomotor activity may be associated with the selective activation of 5-HT1C, or possibly 5-HT1B, receptors. Language of Publication English Unique Identifier 89216569 -------------------------------------------------------------------------------- Title Discriminative stimulus properties of the serotonin agonist 1-(3-trifluoromethylphenyl)piperazine (TFMPP). Author Glennon RA; McKenney JD; Young R Source Life Sci, 1984 Oct 1, 35:14, 1475-80 Abstract Using a standard two-lever drug discrimination procedure, twelve rats were trained to discriminate 1.0 mg/kg of the serotonin (5-HT) agonist TFMPP from saline. Once trained, the animals displayed a dose-related decrease in discriminative performance upon administration of lower doses of TFMPP. Tests of stimulus generalization were performed using the purported 5-HT agonist RU-24, 969 and 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM). While TFMPP produced stimulus effects similar to those of RU-24,969, these effects seem to be dissimilar to those of DOM. The results of the present study suggest that the discriminative stimulus effects of TFMPP may involve a 5-HT1-related mechanism. Language of Publication English Unique Identifier 85011865 -------------------------------------------------------------------------------- Title Penile erection and yawning induced by 5-HT1C receptor agonists in male rats: relationship with dopaminergic and oxytocinergic transmission. Author Stancampiano R; Melis MR; Argiolas A Address Bernard B. Brodie Department of Neuroscience, University of Cagliari, Italy. Source Eur J Pharmacol, 1994 Aug 11, 261:1-2, 149-55 Abstract 1-(3-Chlorophenyl)piperazine (m-CPP) (0.1-4 mg/kg s.c.) and N-(3-trifluoromethylphenyl)-piperazine (TFMPP) (0.5-4 mg/kg s.c.), 5-HT1C receptor agonists, but not 8-hydroxy-dipropylamino-tetralin (8-OH-DPAT) (0.1 and 0.2 mg/kg s.c.), a 5-HT1A receptor agonist, induced penile erection and yawning with a U-inverted dose-response curve in male rats. The maximal effect was found with 0.5 mg/kg s.c. of m-CPP and with 1 mg/kg s.c. of TFMPP. The m-CPP (0.5 mg/kg s.c.) and TFMPP (1 mg/kg s.c.) responses were prevented by mianserin (0.2 mg/kg s.c.) and by ritanserin (1 mg/kg s.c.) given 15 min before m-CPP and TFMPP. In contrast, m-CPP- or TFMPP-induced penile erection and yawning were not antagonized by haloperidol (0.1 mg/kg s.c.) or by [d(CH2)5Tyr(Me)2,Orn8]vasotocin (5 micrograms i.c.v.). Apomorphine- and oxytocin-induced penile erection, but not yawning, was also antagonized by mianserin and less effectively by ritanserin. The results suggest that 5-HT1C receptor agonist-induced penile erection and yawning are not mediated by increased dopaminergic and/or oxytocinergic transmission, and raise the possibility that a neuronal dopamine-oxytocin-5-HT link is involved in the control of penile erection and not necessarily of yawning in male rats. Language of Publication English Unique Identifier 95094888 -------------------------------------------------------------------------------- Title Properties of some 1-arylpiperazines as antagonists of stereotyped behaviors mediated by central serotonergic receptors in rodents. Author Simansky KJ; Schechter LE Address Department of Pharmacology, Medical College of Pennsylvania at Eastern Pennsylvania Psychiatric Institute, Philadelphia. Source J Pharmacol Exp Ther, 1988 Dec, 247:3, 1073-81 Abstract This investigation evaluated the effects of the 1-arylpiperazines (1-(1-naphthyl)piperazine (1-NP), 1-(2-[4-aminophenyle thyl]-4-[3-trifluoro- methylphenyl]piperazine (PAPP), 1-(3-trifluoromethylphenyl)piperazine (TFMPP) and 1-(3-chlorophenyl)piperazine (mCPP) on head-twitching elicited by central 5-hydroxytryptamine2, (5-HT2) agonists and on the 5-HT motor syndrome associated with stimulating 5-HT1A receptors in rodents. 1-NP (0.25-16.0 mumol/kg i.p.) dose-dependently inhibited head twitching produced by carbidopa (100 mumol/kg i.p.) plus 5-hydroxy-L-tryptophan (1000 mumol/kg i.p.) in mice. Pretreatment with 4 mumol/kg of 1-NP shifted the entire dose-response curve for head-twitching induced by quipazine (0.33-46.7 mumol/kg i.p.) to the right without reducing locomotor stimulation produced by quipazine (8 mumol/kg) in mice placed in novel photocell cages. 1-NP, PAPP, TFMPP and mCPP (8 mumol/kg) antagonized twitching after 5-methoxy-N,N-dimethyltryptamine (100 mumol/kg i.p.) or 5-hydroxy-L-tryptophan. In rats, these arylpiperazines (1-32 mumol/kg) dose-dependently antagonized twitching elicited by quipazine (10 mumol/kg) without producing correlated alterations in locomotion. 1-NP, PAPP, and mCPP were equipotent and 6-fold more potent than TFMPP against twitching. None of these arylpiperazines caused twitching. 1-NP (4 mumol/kg) also antagonized twitching following the direct 5-HT2 agonist 1-(2,5-dimethoxy-4-iodophenyl)- 2-aminopropane (6 mumol/kg i.p.) but not after the thyrotropin releasing hormone analog MK-771 (20 mumol/kg i.p.) in rats. Larger doses of 1-NP (4-32 mumol/kg) and PAPP (64 mumol/kg) but not TFMPP or mCPP ( -------------------------------------------------------------------------------- Title Serotonergic mediation of fenfluramine discriminative stimuli in fawn-hooded rats. Author Schechter MD Address Department of Pharmacology, Northeastern Ohio Universities, College of Medicine, Rootstown 44272, USA. Source Life Sci, 1997, 60:6, PL83-90 Abstract Fenfluramine, a drug that induces increased synaptic serotonin, was used to train Fawn-Hooded rats in a drug discrimination paradigm. This strain of rats is thought to possess a genetic serotonin storage abnormality. The intent of the study was to see if the Fawn-Hooded rat was similar or dissimilar to the more frequently used strain of Sprague-Dawley rat in its ability to learn to discriminate 2.0 mg/kg fenfluramine administered intraperitoneally. In addition, drugs presumed to work upon central serotonergic neurons were given to the fenfluramine-trained Fawn-Hooded rats to investigate if the cueing properties of the training drug generalized to other agents. Results indicate that the Fawn-Hooded rats learn to discriminate fenfluramine from its vehicle at the same rate, and with a similar sensitivity to lower doses, as do the Sprague-Dawley rats. Furthermore, fenfluramine was shown to completely generalize to MDMA (over 90%); TFMPP, m-CPP, quipazine and fluoxetine produced intermediate results (over 70%) and 5-MeODMT and ibogaine were vehicle-like (less than 70%). As these results coincide with those previously found in Sprague-Dawley rats, the conclusion is that the functional capacity to discriminate fenfluramine appears to be like that of other rat lines, and serotonergically-mediated, in the Fawn-Hooded rat. Suggestions to explain these results are offered and discussed. Language of Publication English Unique Identifier 97183730 -------------------------------------------------------------------------------- Title Serotonergic-dopaminergic mediation of 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy"). Author Schechter MD Address Department of Pharmacology, Northeastern Ohio Universities, College of Medicine, Rootstown 44272. Source Pharmacol Biochem Behav, 1988 Dec, 31:4, 817-24 Abstract A series of three experiments were conducted to investigate the possible serotonergic and dopaminergic mediation of the discriminative stimulus properties of the "designer" drug MDMA. In Experiment 1, rats trained to discriminate 1.5 mg/kg (+/-)-MDMA from its vehicle at 20 min postadministration were shown to generalize to another drug of abuse, N-ethyl-3,4-methylenedioxyamphetamine (MDE) and to the serotonergically-active agents norfenfluramine and TFMPP. In contrast, testing of various dopaminergically-active agonists did not result in MDMA-like responding. In Experiment 2, dopaminergic and serotonergic antagonist were employed to observe their effect upon MDMA discrimination at 20 min postinjection. The serotonin antagonist pirenperone significantly decreased MDMA discrimination, whereas the dopamine decreasing drugs CGS 10746B and haloperidol had no effect. In Experiment 3, another group of rats were trained to discriminate MDMA at 105 min postadministration to investigate if, at this (later) time, the dopaminergic properties of MDMA may be more salient. Indeed, the dopaminergically-active drugs had a heightened effect upon MDMA at this later time, although the serotonergic component of the MDMA discriminative stimulus was predominant. The results suggest that the effects of MDMA at 20 min postadministration are solely serotonergic in nature. At 105 min postinjection there appears to be the presence of a weak dopaminergic component. This biphasic serotonergic-then-dopaminergic action of MDMA may explain the reported human experience with the drug, as well as the often controversial results in the literature. Language of Publication English Unique Identifier 89297126 -------------------------------------------------------------------------------- Title Serotonergic modulation of the rat pup ultrasonic isolation call: studies with 5HT1 and 5HT2 subtype-selective agonists and antagonists. Author Winslow JT; Insel TR Address Laboratory of Clinical Science, National Institute of Mental Health, NIHAC, Poolesville, MD 20837. Source Psychopharmacology (Berl), 1991, 105:4, 513-20 Abstract A modulatory role for serotonin has been described for the development and expression of the ultrasonic call of infant rat pups during brief maternal separations. In previous studies, serotonin reuptake inhibitors selectively reduced the rate of calling following acute administration to 9-11-day-old pups and a serotonin neurotoxin (MDMA) systematically disrupted the development of ultrasonic vocalizations but not other measures of motor development. In the current studies, we extended our investigations to include drugs with purported receptor subtype selectivities. Consistent with previous reports, acute administration of 5HT1A agonists buspirone and 8-OH-DPAT [+/-)-8-hydroxy-2-(di-N-propylamino)tetralin) reduced the rate of calling at doses which did not affect motor activity or core body temperature. The rate reducing effects of buspirone persisted up to 1 but not 2 h after injection. Administration of purported 5HT1B receptor agonists, CGS12066B (7-trifluoromethyl-4(4-methyl-1-piperazinyl)-pyrrolo[1,2-a] quinoxaline) and TFMPP (1-[3-fluoromethyl)phenyl]-piperazine) increased the rate of calling depending on the specificity of the drug for the 5HT1B receptor. d,l-Propranolol, a 5HT1 receptor antagonist, blocked the effects of both 8-OH-DPAT and TFMPP. m-CPP (1-(3-chlorophenyl)piperazine) and DOI [+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane), drugs with putative actions at 5HT1C and 5HT2 receptor sites both decreased calling but differed according to their effects on motor activity. Ritanserin, a 5HT2 and 5HT1C antagonist, produced a dose-related increase in call rate. A dose of ritanserin with no apparent intrinsic effects effectively antagonized DOI rate reducing effects but potentiated the rate reducing effects of m-CPP.(ABSTRACT TRUNCATED AT 250 WORDS) Language of Publication English Unique Identifier 92123829 ================================================================================ Effects of benzylpiperazine derivatives on the acute effects of 3,4-methylenedioxymethamphetamine in rat brain. Source: Neurosci Lett, 1993 Apr 2, 152:1-2, 17-20 Abstract The reduction of 5-hydroxytryptamine (5-HT) in rat brain 3 h after administration of 3,4-methylenedioxymethamphetamine (MDMA) was attenuated significantly by coadministration of benzylpiperazine derivatives (p-nitrobenzylpiperazine, p-chlorobenzylpiperazine and 1-piperonylpiperazine), which were weak inhibitors of [3H]5-HT uptake into rat brain synaptosomes. However, the coadministration of desipramine and imipramine which were more potent 5-HT uptake inhibitors than these benzylpiperazines, did not attenuate the reduction of 5-HT by MDMA. These results suggest that these benzylpiperazines might inhibit the acute effects of MDMA by a novel neuropharmacological effect other than 5-HT uptake inhibition. - - - - - Effects of benzylpiperazine derivatives on the neurotoxicity of 3,4-methylenedioxymethamphetamine in rat brain. Source: Brain Res, 1992 Sep 11, 590:1-2, 341-4 Abstract The neurotoxicity of 3,4-methylenedioxymethamphetamine (MDMA) in rat brain was attenuated significantly by coadministration of several benzylpiperazines (p-nitrobenzylpiperazine, p-chlorobenzylpiperazine and 1-piperonylpiperazine), which were weak inhibitors for [3H]6-nitroquipazine binding to the 5-hydroxy- tryptamine (5-HT) transporter in rat brain. These results suggest that these benzylpiperazines may inhibit the MDMA-induced neurotoxicity by a novel neuropharmacological effect other than 5-HT uptake inhibition. - - - - - Comparison of serotonin agonistic and antagonistic activities of a new antidepressant agent Trelibet (EGYT-475) and its metabolite EGYT-2760 on isolated rat fundus. Source: Acta Physiol Hung, 1991, 78:3, 201-9 Abstract The effects of Trelibet (EGYT-475, N-benzyl-piperazine-picolinyl-fumarate) and its active metabolite (EGYT-2760, N-benzyl-piperazine) on the serotoninergic responses of rat stomach fundus were investigated and compared with those of MCPP (m-chlorophenyl-piperazine) which is the common metabolite of the arylpiperazine antidepressants Trazodone and Etoperidone. The contraction inhibitory potencies of the agents were determined on the equipotent contractions (EC50) to serotonin (5-HT) and prostaglandin F2 alpha (PGF2 alpha). Isotonic contractile responses to 5-HT were not affected by EGYT-475, however, both EGYT-2760 and MCPP produced concentration related and reversible inhibition of the serotoninergic responses. The IC50 values for EGYT-2760 and MCPP were 40.5 +/- 7.5 mumol/l and 125 +/- 35 nmol/l, respectively. The inhibition was selective for the serotoninergic responses, as the equipotent responses to PGF2 alpha were not affected. EGYT-2760 and MCPP displayed not only 5-HT antagonistic, but also partial agonistic activities on the rat fundus preparation. Maximum contractile response of the fundus preparation to MCPP was approximately 25%, to EGYT-2760 was 10% of the maximum response to 5-HT. - - - - - Benzylpiperazine derivatives. XI. Synthesis of compounds related to the metabolites of 1-[bis(4-fluorophenyl)methyl]-4-( 2,3,4-trimethoxybenzyl)piperazine * 2 HCl (KB-2796). Source: Chem Pharm Bull (Tokyo), 1989 Nov, 37:11, 3122-4 Abstract The metabolites of 1-[bis(4-fluorophenyl)methyl]-4-(2,3,4-trimethoxybenzyl)- piperazine dihydrochloride (KB-2796, 1), a cerebral vasodilator, and related compounds were synthesized to confirm the proposed structures. The structures of the metabolites (3-5) in rats were identified by means of synthesis of the authentic compounds. - - - - - Synthesis and evaluation of phenyl- and benzoylpiperazines as potential serotonergics. Source: J Med Chem, 1986 May, 29:5, 630-4 Abstract The binding of a series of phenylpiperazines (3) and benzoylpiperazines (4) to central serotonin (5-HT) sites was investigated. Several derivatives of 3 displayed nanomolar affinities for 5-HT1 sites, whereas derivatives of 4 were essentially inactive both at 5-HT1 and 5-HT2 sites. 1-(2-Methoxyphenyl)piperazine (2-MPP, 3a) was found to possess an affinity (Ki = 35 nM) for 5-HT1 sites comparable to that of the recognized 5-HT agonist 1-[3-(trifluoromethyl)phenyl]- piperazine (TFMPP) (Ki = 20 nM); 3a also displayed a 100-fold selectivity for 5-HT1 sites (as compared to 8-fold for TFMPP). In tests of stimulus generalization using rats trained to discriminate TFMPP (ED50 = 0.17 mg/kg) from saline, 3a was found to be nearly equipotent (ED50 = 0.22 mg/kg) with the training drug. These results suggest that 3a may be a novel and more selective 5-HT1 agonist than TFMPP. - - - - - Dyskinetic phenomena caused by the intrastriatal injection of phenylethylamine, phenylpiperazine, tetrahydroisoquinoline and tetrahydronaphthalene derivatives in the guinea pig. Source: Eur J Pharmacol, 1975 Mar, 31:1, 94-109 Abstract The intrastriatal injection of dopamine-like compounds in the guinea pig caused the development of abnormal involuntary movements (dyskinesias) which were observed as facial grimacing, biting/gnawing/licking, severe hear and neck twisting, limb movements, whole body rocking, head and neck rocking and marked locomotor hyperactivity. With the exception of the whole body and head and neck rocking movements the dyskinesias were specifically induced by dopamine-like agents. The most conspicuous dyskinesias which followed the administration of phenylethylamine derivatives were the movements of biting/gnawing/licking and the development of marked locomotor hyperactivity. This effect was shown to be highly specific for dopamine. Tetrahydroisoquinohydroxy-1,2,3,4- tetrahydronaphthalene (ADTN) caused locomotor hyperactivity and gnawing/biting/licking dyskinesias. Of all compounds investigated 1-(3,4-dihydroxyphenyl)pierazine (DHPP) induced the most marked dyskinetic disturbances upon intrastriatal injection: intense facial grimacing, biting/gnawing/licking, head and neck twisting and limb movements were observed although the locomotor hyperactivity was absent. Of the 1-phenylpiperazine derivatives examined, dyskinetic activity was only demonstrated using compounds with a hydroxyphenyl substitution. Results are discussed in terms of the structure--activity relationships for the stimulation of different types of dopamine receptive structures within the neostriatum. - - - - - Central serotoninmimetic action of phenylpiperazines. Source: Pol J Pharmacol Pharm, 1980 Jul-Aug, 32:4, 495-504 Abstract Studies of 1-(m-chlorophenyl)-piperazine (m-CPP), 1-(p-chlorophenyl)- piperazine (p-CPP) and 1-phenylpiperazine (PP) were carried out on rats, mice and rabbits in order to assess their stimulatory effect on the central serotonin system. It was found out that m-CPP and p-CPP evoked a characteristic syndrome in the mouse behavior. All the phenylpiperazine derivatives stimulated the flexor reflex in the spinal rat and evoked hyperthermia in rats at a high ambient temperature (28 degrees C) and in rabbits. The above effects were abolished by cyproheptadine, a drug blocking the serotonin receptors. The obtained results indicate that the phenylpiperazine derivatives studied have a central serotoninmimetic action. - - - - - The cardiovascular and autonomic properties of N-phenylpiperazine (NPP) Source: J Pharmacol Exp Ther, 1982 Oct, 223:1, 110-9 Abstract A number of isolated tissue and intact animal models were utilized to investigate in more detail the cardiovascular actions of N-phenylpiperazine (NPP), a known compound having adrenergic blocking properties. In isolated tissues its autonomic profile is characterized by alpha and beta adrenergic blocking activity. Compared to other beta receptor antagonists, NPP displays moderate in vitro beta-1 blockade in guinea-pig atria. Cumulative administration of NPP (0.1--0.3 mg/kg i.v.) in the intact dog also produces dose-dependent inhibition of myocardial contractility following isoproterenol administration. The oral antihypertensive potency of NPP in the deoxycorticosterone acetate hypertensive rat is compared with phenoxybenzamine and labetalol. Its profile is similar to labetalol but differs from phenoxybenzamine, causing a fall in blood pressure and a decrease in heart rate. Hemodynamic data obtained with NPP in the anesthetized animal reveal a complex cardiovascular profile involving the interactions of the sympathetic nervous system. Canine hind limb perfusion studies using cumulative doses (0.1--0.3 mg/kg i.v.) appear to preclude a direct vasodilator mechanism in the reserpinized-pretreated animal. In other studies, nonselective vasoconstrictor responses induced by exogenous administration of norepinephrine and lumbar sympathetic nerve stimulation are inhibited to the same degree by NPP (0.1--10 mg/kg i.v.) autonomic interactions with NPP in the nictitating membrane provide evidence for inhibition of neuronal catecholamine uptake and catecholamine release. From the data obtained in the present study, it is suggested that NPP has a predominant influence on the response of the sympathetic nervous system to provide a unique cardiovascular profile. The manner in which blood pressure is regulated by either direct or nonselective mechanisms will be discussed. - - - - - Structure-activity relationship studies of CNS agents, Part 23: N-(3-phenyl- propyl)- and N-[(E)-cinnamyl]-1,2,3,4-tetrahydroisoquinoline mimic 1-phenylpiperazine at 5-HT1A receptors. Source: Arch Pharm (Weinheim), 1995 Jul, 328:7-8, 604-8 Abstract The 5-HT1A receptor affinities and ionization constants of a set of 1-arylpiperazine (4) 1,2,3,4-tetrahydroisoquinoline (6), and -quinoline (7) containing N-(omega-arylalkyl) or N-(E)-cinnamyl substituents as well as two morpholine derivatives (8a, 8b) were determined. It was shown that some tetrahydroisoquinoline (6c, 6d) and morpholine (8a) derivatives were 5-HT1A ligands equipotentto 1-phenylpiperazine (4a) and 1,2,3,4,4a,5- hexahydropyrazino [1,2-a]indole (5). On the basis of molecular modelling studies it was also demonstrated that 6c, 6d and 8a mimicked very well the reference structures of 4a and its rigid analog 5. Another, more complex 1,2,3,4-tetrahydroisoquinoline derivative 3, which served as a model compound to confirm the previously reported 5-HT1A binding mode of derivatives 1a-d and 2, had the highest 5-HT1A affinity (Ki = 6.7 +/- 0.5 nM) of all the investigated compounds. - - - - - Meta-chlorophenylpiperazine induced changes in locomotor activity are mediated by 5-HT1 as well as 5-HT2C receptors in mice. Source: Eur J Pharmacol, 1998 Jan, 341:2-3, 135-8 Abstract 1-(Meta-chloro)phenylpiperazine (m-CPP) is a 5-HT receptor agonist which has been purported to be relatively selective for the 5-HT2C receptor. In particular, the hypolocomotion produced by m-CPP has been suggested to be mediated by 5-HT2C receptors. m-CPP binds with high affinity to 5-HT1 as well as 5-HT2 receptors, thus effects of m-CPP on locomotor activity may be due to the physiologic summation of the actions of m-CPP at 5-HT1 as well as 5-HT2 receptors. The present study investigated the effects of m-CPP alone and in the presence of the 5-HT2 receptor antagonist 6-methyl- 1-(-methyethyl)-ergoline-8beta-carboxylic acid 2-hydroxy-1-methylpropyl ester maleate (LY53857), the 5-HT1A receptor antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethyl]-N-(2pyridinyl)cyclohexane- carboxamide trihydrochloride (WAY 100,635), and the 5-HT(1B/1D) receptor antagonist 2'-methyl-4'-(5-methyl-[1,2,4]oxadiazol-3-yl)-biphenyl- 4-carboxylic acid [4-methoxy-3-(4-methyl-piperazin-1-yl)-phenyl]amide (GR 127935) on locomotor activity. Administration of m-CPP alone (0.3-10 mg/kg) produced a dose-related decrease in locomotor activity. The 5-HT(1B/1D) receptor antagonist GR 127935 (3.0 mg/kg) in combination with m-CPP produced a slight leftward shift of the dose-response curve of m-CPP. The 5-HT1A receptor antagonist WAY 100,635 (1.0 mg/kg) in combination with m-CPP did not alter the m-CPP dose-response curve. The non-selective 5-HT2 receptor antagonist LY53857 (1.0 mg/kg) in combination with m-CPP unmasked a hyperlocomotion produced by m-CPP. Furthermore, the hyperlocomotion produced by m-CPP in the presence of LY53857 (1.0 mg/kg) was blocked by both the 5-HT(1B/1D) receptor antagonist GR 127935 (3.0 mg/kg) and the 5-HT1A receptor antagonist WAY 100,635 (1.0 mg/kg). The present results demonstrate that the hyperlocomotion seen with the combination of m-CPP and LY53857 is mediated by 5-HT1 receptors. Taken together the data indicate that m-CPP affects locomotor activity by the physiologic summation of agonist activity at the 5-HT2C receptor as well as the 5-HT1 receptor family. - - - - - Application of a novel phenylpiperazine formation reaction to the radiosynthesis of a model fluorine-18-labeled radiopharmaceutical (18FTFMPP). Source: Nucl Med Biol, 1997 Apr, 24:3, 269-73 Abstract The labeled serotonin agonist 3-[18F]fluoro-N-(alpha,alpha,alpha- trifluoro-m-tolyl)piperazine (18FTFMPP) was prepared rapidly using the labeling procedure for trifluorotoluenes, [18F]fluoro-for-nitro exchange, followed by an alumina-supported bis-alkylation. After normal-phase HPLC purification, the labeled product was obtained in 20-32% (n = 20) decay- corrected radiochemical yield with a radiochemical purity > 98% and a specific activity of 100 GBq/mumol. The synthesis time including purification was 3 h. The receptor binding affinity of FTFMPP to rat brain membranes was found to be similar to that of the nonfluorinated parent compound (TFMPP). Although TFMPP has been proposed by others as an agent for the imaging of serotonin receptors, only minimal receptor- mediated uptake was observed. - - - - - Modulation of the discriminative stimulus properties of cocaine: comparison of the effects of fluoxetine with 5-HT1A and 5-HT1B receptor agonists. Source: Neuropharmacology, 1997 Mar, 36:3, 373-81 Abstract The present investigation examined the ability of serotonin (5-HT) agonists to substitute for, or alter (i.e. enhance or antagonize), the discriminative stimulus properties of a moderately low dose of cocaine (5 mg/kg) utilizing a two-lever, water-reinforced FR 20 drug discrimination procedure in rats. In substitution tests, the 5-HT1A receptor partial agonists buspirone and gepirone, the 5-HT1A/B receptor agonist RU 24969 and the 5-HT1B/2C receptor agonist m-trifluoromethyl- phenylpiperazine (TFMPP) failed to substitute for the cocaine stimulus, although RU 24969 did engender a maximum of 72% cocaine-lever responding. Fluoxetine (4 mg/kg) engendered primarily saline-appropriate responding. In combination tests, a fixed dose of either fluoxetine (4 mg/kg), RU 24969 (0.5 mg/kg) or TFMPP (0.5 mg/kg) produced a leftward shift in the cocaine dose-response curve (0.313-5 mg/kg). In contrast, buspirone (2.5-20 mg/kg) resulted in a dose-dependent attenuation (approximately 60% reduction) of the cocaine stimulus. Moreover, a dose of 10 mg/kg of buspirone co-administered with various doses of cocaine (1.25-10 mg/kg) engendered a rightward shift in the cocaine dose-response curve. Gepirone in combination with cocaine neither enhanced nor antagonized the cocaine discriminative stimulus. Whereas 5-HT agonists do not fully substitute for cocaine, the present results demonstrate that 5-HT1B, but not 5-HT1A, receptor agonists can modulate the discriminative stimulus properties of cocaine in a manner similar to that observed following administration of the 5-HT reuptake inhibitor fluoxetine. The ability of buspirone, but not gepirone, to attenuate the cocaine stimulus probably reflects its dopamine (DA) D2 receptor antagonist properties and not its efficacy at 5-HT1A receptors. - - - - - The influence of serotoninergic drugs on dopaminergic neurotransmission in rat substantia nigra, striatum and limbic forebrain in vivo. Source: Naunyn Schmiedebergs Arch Pharmacol, 1992 Jul, 346:1, 12-9 Abstract The effects of serotoninergic drugs on dopaminergic neurotransmission in the substantia nigra, the striatum and the limbic forebrain of rat have been investigated. The accumulation of 3-methoxytyramine (3-MT) following inhibition of monoamine oxidase with pargyline was used as an indirect measure of dopamine (DA) activity in vivo. The effects of the following serotoninergic drugs were tested: the 5-HT1A receptor agonist 8-OH-DPAT, the 5-HT1B receptor agonist trifluoromethyl-phenylpiperazine (TFMPP), CGS 12066 B and RU 24969, the 5-HT1A/1B antagonist (+/-)pindolol, the 5-HT2/1C receptor antagonist ritanserin, the 5-HT2/1C receptor agonist DL-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), the 5-HT3 receptor antagonist BRL 43694, the unselective 5-HT receptor antagonist methiothepin, and carbidopa + L-5-hydroxytryptophan (L-5-HTP) to achieve a general, unselective stimulation of multiple 5-HT receptors. In the substantia nigra, carbidopa + 5-HTP treatment increased the 3-MT accumulation by 26% and decreased the DA concentration to 67% of controls, tentatively suggesting a 5-HTP-induced displacement of nigral DA. A minor, non dose-related reduction in nigral 3-MT was seen after the 5-HT1A receptor agonist 8-OH-DPAT. None of the other serotonin receptor acting drugs induced any pronounced effect on the nigral 3-MT accumulation. Taken together, the findings provide little support for the idea that one single 5-HT receptor subtype serves a modulatory function on DA activity in the substantia nigra. In the striatum and the limbic forebrain, trifluoromethyl-phenylpiperazine dose-dependently increased the 3-MT accumulation to maximally 200%-220% of controls. (ABSTRACT TRUNCATED AT 250 WORDS) - - - - - Novel 1-phenylpiperazines and 4-phenylpiperidines as high-affinity sigma ligands. Source: J Med Chem, 1991 Dec, 34:12, 3360-5 Abstract Sigma receptors may represent an exciting new approach for the development of novel psychotherapeutic agents. Unfortunately, many of the commonly used sigma ligands lack selectivity (e.g., many bind at phencyclidine or dopamine receptors) or suffer from other serious drawbacks. Recently, we described a series of 2-phenylaminoethanes that bind at sigma receptors with high affinity and selectivity. Because there is evidence that 1-phenylpiperazines can structurally mimic the 2-phenylaminoethane moiety, we prepared a series of 1-phenylpiperazines and related analogues and incorporated structural features already shown to enhance the sigma binding of the 2-phenylaminoethanes. Several of these derivatives bind at sigma receptors with high affinity (Ki = 1-10 nM) and lack appreciable affinity for phencyclidine and dopamine receptors. In as much as certain of these agents structurally resemble the high-affinity, but nonselective, sigma ligand haloperidol, and because they bind with 10 times the affinity of haloperidol, we have apparently identified what appears to be the primary sigma pharmacophore of that agent. - - - - - 5-HT1A receptor blockade increases penile erections induced by 5-HT agonists. Source: Neuroreport, 1993 Dec 13, 5:3, 229-30 Abstract Indirect serotonergic agonists, whether promoters of 5-HT release such as fenfluramine (5 mg kg-1) or inhibitors of 5-HT uptake such as fluoxetine (10 mg kg-1), elicited in rats penile erections at a modest but significant level. Their effects were markedly potentiated by the beta-blocker tertatolol, (0.6-5 mg kg-1) which displays 5-HT1A receptor blocking activity, but not by the beta-blocker labetalol (6.25 and 25 mg kg-1), which lacks such activity. In addition, tertatolol, but not labetalol, potentiated penile erections induced by meta-chloro-phenylpiperazine (1 mg kg-1). Thus, it appears that increasing serotonergic transmission increases only moderately penile erections because of the functional opposition exerted by 5-HT1A (inhibition) and 5-HT1C (activation) serotonin receptors on this response. - - - - - Activity of aromatic substituted phenylpiperazines lacking affinity for dopamine binding sites in a preclinical test of antipsychotic efficacy. Source: J Med Chem, 1989 May, 32:5, 1052-6 Abstract Generally, antipsychotic agents are dopamine receptor blocking agents that also block conditioned avoidance responding (CAR) in the rat. Recently, however, both (Q-methoxyphenyl)piperazine (OMPP, 1h) and (m-chlorophenyl)piperazine (MCPP, 1o) have been reported to block conditioned avoidance responding in the rat although neither has dopamine receptor blocking properties. The present paper examines the behavioral and biochemical profile of a number of additional substituted phenylpiperazines. None of the phenylpiperazines tested demonstrated high affinity for either dopamine D-1 or D-2 receptor sites, yet many were effective in blocking CAR. The results suggest that the phenylpiperazines may be effective antipsychotic agents without blocking dopamine receptors. Moreover, the active compounds did demonstrate activity in displacing ligand binding to serotonin receptors. Receptor binding profiles were determined for 5-HT-1A and 5-HT-1B binding sites as well as for 5-HT-2 sites. The data from this preclinical test suggest these phenylpiperazines might be effective antipsychotic agents acting via a nondopaminergic mechanism of action. - - - - - Block of conditioned avoidance responding in the rat by phenylpiperazines. Source: Eur J Pharmacol, 1988 Nov 1, 156:2, 223-9 Abstract Ortho-methoxyphenylpiperazine (OMPP) and meta-substituted chlorophenyl- piperazine (MCPP) blocked conditioned avoidance responding (CAR) in the rat (ED50 values = 5.6 (4.6, 7.3) and 2.4 (1.9, 2.9) mg/kg i.p. (95% confidence limits), respectively) without markedly altering escape responding. Since this test predicts antipsychotic efficacy, the piperazines were examined in radioligand binding assays and found to have no affinity for dopamine (DA) binding sites, but were active at serotonin binding sites. OMPP displaced ligands for the 5-HT1A binding site with high affinity (Ki = 9.5 (5.4, 17.9) nM) but was inactive at 5-HT2 sites (Ki greater than 1000 nM). MCPP, on the other hand, displaced ligands for 5-HT1, 5-HT1A and 5-HT2 binding sites with similar potencies (Ki values = 25 (3, 67), 23 (14, 40) and 40 (33, 48) nM, respectively). Pretreatment with metergoline (1.0 mg/kg i.p. -30 min) reduced MCPP- but not OMPP- induced block of CAR. OMPP, on the other hand, acted as a DA receptor antagonist in vivo blocking amphetamine-induced stereotyped behavior, whereas MCPP did not. Neither produced catalepsy even given in doses 8-10 times those required to block CAR. Insofar as these compounds lack antidopaminergic activity in vivo, yet are active in a test (CAR) predictive of antipsychotic activity in which DA receptor antagonists are active, they may be novel antipsychotic agents, or, perhaps, false positives in the CAR paradigm. - - - - - Agonist/antagonist activities of arylpiperazines at human platelet 5HT2 receptors. Source: J Pharmacol Exp Ther, 1988 Dec, 247:3, 965-70 Abstract A series of arylpiperazines was examined for structure-function relationships at the human platelet serotonin (5-HT) receptor. Amplification of ADP-induced aggregation was used to measure 5-HT receptor activation. The platelet serotonergic agonists 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), 5-HT and 5-methoxytryptamine (5-MeOT) and the antagonist ketanserin were used for comparison of potency and amplitude of response. All arylpiperazines, including the parent compound phenylpiperazine (PP) showed antagonist activity. The monosubstituted phenylpiperazines acted only as antagonists, and electron-withdrawing substituents markedly enhanced activity. Modification of PP by addition of another phenyl ring or benz-fusion also enhanced antagonist activity. Benz-fusion at the b face of PP (1-NP) yielded greater antagonist potency than benz-fusion at the c face (2-NP). The latter modification, however, also conferred a variable agonist activity with a very weak response. In contrast, the heteroaromatic piperazines consistently demonstrated concentration dependent mixed antagonist-agonist activity. These compounds were weak agonists compared with 5-HT, 5-MeOT and DOI, although the amplitude of the quipazine response was similar to DOI. This study demonstrates that the arylpiperazines, which are variably selective for the multiple brain 5-HT receptors, are all antagonists on the platelet 5-HT receptor. The antagonist activity is markedly increased by ring monosubstitution or aryl modification. Compared with the monosubstituted analogues, antagonist activity is decreased by heteroaromatic modification or by the addition of an N-aminophenethyl group to the 4-position nitrogen. Weak agonist activity can be conferred by heteroaromatic modification. - - - - - Effects of fenfluramine, m-chlorophenylpiperazine, and other serotonin- related agonists and antagonists on penile erections in nonhuman primates. Source: Life Sci, 1988, 43:16, 1297-303 Abstract Fenfluramine, m-chlorophenylpiperazine (m-CPP), 1-phenylpiperazine, and the buspirone metabolite, 1-(2-pyrimidyl)piperazine given intravenously to adult rhesus monkeys regularly elicited penile erections. In contrast, serotonin (5-HT) agonists with 5-HT1A site specificity (8-OH-DPAT, buspirone) as well as trazodone, ritanserin, and metergoline were no different from saline in producing penile erections. Fenfluramine's effects were blocked by the 5-HT2 antagonists, ritanserin and metergoline, while m-CPP's effects were not blocked by the peripheral 5-HT antagonist, xylamidine, indicating that tumescence can be elicited by serotonergic agents which act at non-5-HT1A sites in the central nervous system. - - - - - Behavioral tolerance to one effect of the serotonergic agonist TFMPP. Source: Prog Neuropsychopharmacol Biol Psychiatry, 1992 May, 16:3, 361-8 Abstract 1. In mice isolated for one week and observed in pairs with non-isolated mice under a reversed beaker, the serotonergic agonist: 1-3-(trifluoro- methyl)phenylpiperazine (TFMPP) increased the number of escape attempts. 2. A partial tolerance to this effect has been observed in mice which were tested a first time after administration of TFMPP one week sooner. 3. An analysis of this form of tolerance was carried out by changing success- ively and separately each of the events concomitant of this tolerance. 4. The results show that this tolerance is not a pharmacocinetic or a pharmacodynamic one. Observation of the tolerance required the performance of the first test in a drug state. The more likely explanation is that this tolerance results from a conditioned opponent response. - - - - - Biotransformation study of para-substituted phenylpiperazines in beagle dogs by gas chromatography-mass spectrometry. Source: Xenobiotica, 1991 Oct, 21:10, 1371-84 Abstract 1. Beagle dogs were treated orally (10 mg/kg) with para-chloro-, para-fluoro- and para-methyl-phenylpiperazine derivatives, and urine was collected for 72 h after treatment. 2. Metabolites were extracted, converted into trimethylsilyl (TMS) derivatives and examined by g.l.c.-mass spectrometry. 3. The metabolites fall into two main groups, N-desphenylated metabolites, which result from N-desphenylation, and N-phenyl metabolites. 4. Two kinds of hydroxylated metabolites were found. Some lost the original para substituent (Cl, F or CH3); others retained it. 5. These results are consistent with the NIH shift reaction. - - - - - 5-HT-1a and 5-HT-1b selectivity of two phenylpiperazine derivatives: evidence for 5-HT-1b heterogeneity. Source: Life Sci, 1985 Apr 1, 36:13, 1265-73 Abstract The ability of m-trifluoromethylphenylpiperazine (TFMPP) and an N-substituted derivative, LY 165163 (p-NH2-PE-TFMPP), to discriminate 5-HT-1 binding sites labelled by [3H]5-HT is compared in rat corpus striatum and rat cortex. TFMPP displays at least a 30 fold selectivity for the 5-HT-1b subtype. Furthermore, TFMPP reveals heterogeneity within the 5-HT-1b binding sites. TFMPP displays a Kd of 6 nM for approximately two-thirds of the 5-HT-1b binding sites and a Kd of 273 nM for the remaining one third of the 5-HT-1b sites. p-NH2-PE-TFMPP, on the other hand, discriminates the 5-HT-1 sites in a manner similar to spiperone, displaying a 110 fold selectivity for the 5-HT-1a sites. p-NH2-PE-TFMPP displays a Kd of about 3 nM for the 5-HT-1a sites. p-NH2-PE-TFMPP does not discriminate subtypes within the 5-HT-1b binding sites. The significance of the selectivity of these two compounds as well as structurally related compounds is discussed. - - - - - Discriminative stimulus properties of the serotonin agonist 1-(3-trifluoromethylphenyl)piperazine (TFMPP). Source: Life Sci, 1984 Oct 1, 35:14, 1475-80 Abstract Using a standard two-lever drug discrimination procedure, twelve rats were trained to discriminate 1.0 mg/kg of the serotonin (5-HT) agonist TFMPP from saline. Once trained, the animals displayed a dose-related decrease in discriminative performance upon administration of lower doses of TFMPP. Tests of stimulus generalization were performed using the purported 5-HT agonist RU-24, 969 and 1-(2,5-dimethoxy-4-methyl- phenyl)-2-aminopropane (DOM). While TFMPP produced stimulus effects similar to those of RU-24,969, these effects seem to be dissimilar to those of DOM. The results of the present study suggest that the discriminative stimulus effects of TFMPP may involve a 5-HT1-related mechanism. - - - - - Effects of repeated administration of the monoamine oxidase inhibitor phenelzine on the discriminability of d-lysergic acid diethylamide (LSD) and 1-(m-trifluoromethylphenyl) piperazine (TFMPP). Source: Psychopharmacology (Berl), 1986, 89:1, 134-5 Abstract Rats trained to discriminate d-lysergic acid diethylamide (LSD; 0.08 mg/kg) or 1-(m-trifluoromethylphenyl) piperazine (TFMPP; 0.8 mg/kg) were treated with the monoamine oxidase inhibitor (MAOI) phenelzine (10 mg/kg/day) for 7 days. After a 24 h "washout" period, they were challenged with the training drug (and dose) or saline, during extinction test sessions. Following 0.08 mg/kg LSD, LSD-trained rats responded primarily on the saline lever (29% drug-appropriate responding) while, after TFMPP (0.8 mg/kg), TFMPP-trained animals responded on the drug lever (75% drug-appropriate responding). These preliminary data suggest that, if serotonin receptors are involved in the behavioral effects of TFMPP, these receptors differ from those involved in the effects of LSD. - - - - - TFMPP may produce its stimulus effects via a 5-HT1B mechanism. Source: Pharmacol Biochem Behav, 1986 Jan, 24:1, 43-7 Abstract Tests of stimulus generalization were conducted using rats trained to discriminate 1.0 mg/kg of 1-(3-trifluoromethylphen yl)piperazine (TFMPP) from saline in a standard two-lever operant procedure. Generalization of the TFMPP-stimulus was found to occur with fenfluramine and 1-(3-chlorophenyl)- piperazine (mCPP); generalization did not occur with 8-OH DPAT, quipazine, LSD, 5-OMe DMT or 2,5-DMA. Furthermore, the TFMPP-stimulus was not antagonized by pretreatment of the animals with tetrahydrotrazodone (THT). Based on the results of these studies, and on the results of previous binding studies with these same agents, it is suggested that the stimulus properties of TFMPP are mediated primarily via a 5-HT1B mechanism - - - - - Anxiogenic-like effects of mCPP and TFMPP in animal models are opposed by 5-HT1C receptor antagonists. Source: Eur J Pharmacol, 1989 May 30, 164:3, 445-54 Abstract 1-(3-chlorophenyl)piperazine (mCPP) and 1-[3-(trifluoromethyl)phenyl]- piperazine (TFMPP) (0.1-1.0 mg/kg) reduce total interaction time in a rat social interaction test under low light familiar conditions and its following components; grooming, following, crawling over, fighting, sniffing. Locomotion was only reduced by the highest dose of mCPP. mCPP also reduced activity in the light but not total locomotion in a light/dark transition test. These results suggest that mCPP (and TFMPP) are anxiogenic but not sedative in these tests. The effect of mCPP on social interaction was blocked by three antagonists which share a high affinity for 5-HT1C and 5-HT2 receptors: mianserin, cyproheptadine and metergoline but not by the 5-HT2 antagonists ketanserin or ritanserin or the 5-HT1A and 5-HT1B antagonists cyanopindolol and (-)-propranolol. It was prevented by a low (0.05 mg/kg) but not by a high (1.0 mg/kg) dose of ICS 205,930 a specific 5-HT3 antagonist reported to be anxiolytic at low doses. It was also prevented by chronic pretreatment with the anxiolytic drug chlordiazepoxide. These results argue for an anxiogenic action of mCPP mediated by 5-HT1C receptors. Since the chronic chlordiazepoxide pretreatment did not prevent the hypolocomotion or hypophagia induced by mCPP at high dosage (5 mg/kg) these latter effects are unlikely to be secondary to anxiety. - - - - - Discriminative stimulus properties of m-chlorophenylpiperazine. Source: Pharmacol Biochem Behav, 1993 May, 45:1, 221-3 Abstract Stimulus control was established in a group of 10 rats using a dose of m-chlorophenylpiperazine (MCPP) of 0.8 mg/kg, administered IP, 15 min before training. A two-lever operant task using a fixed-ratio 10 schedule of sweetened milk reinforcement was used. Based upon a criterion for the presence of stimulus control of five consecutive sessions during which 83% or more of all responses were on the appropriate lever, a mean of 27 sessions was required to reach criterion performance. Response rates were significantly suppressed by the training dose of MCPP (14 responses/min) as compared with saline sessions (38 responses/min). Subsequent to the establishment of stimulus control, tests of generalization were conducted with m-trifluoromethylphenylpiperaz ine (TFMPP), 6-chloro-2-(1-piperazinyl)- pyrazine (MK-212), and 5-methoxy-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (RU-24969). MCPP generalized completely to MK-212 and TFMPP at doses of the latter drugs of 0.7 and 1.0 mg/kg, respectively. Maximum generalization to RU-24969 was 67% at a dose of 1.0 mg/kg but only 4 of 10 subjects completed the test session. The present results indicate that MCPP is efficacious as a discriminative stimulus. In addition, because of MCPP's relative selectivity for the 5-hydroxytryptamine c(5-HT1C) receptor subjects trained with MCPP may prove valuable in assessing the respective functional contributions of 5-HT1C sites to the actions of a variety of serotonergic agents. ================================================================================