Future Synthetic Drugs of Abuse
Donald A. Cooper
Drug Enforcement Administration
It seems likely that primitive man wished at times
to escape his reality and most probably found some
natural drug to facilitate this desire. In fact, abuse of
the coca leaf and the opium poppy is thought to have
been practiced for at least the last 3400 years (Lathrap
1976; Rosengarten 1969) and the use of peyote may
have been known as early as 1000 BC (Schultes 1938;
1940). Perhaps due in part to the long history of
opiate products, one of the first derivatives of a
natural drug to be used pharmaceutically was heroin.
The acceptance of heroin as a pharmaceutical was
primal in establishing the concept that certain structural
modifications of physiologically active compounds
can result in new compounds which cause
biological responses which are not only similar, but
are enhanced as compared to those of the parent
compounds. Other works such as the structural elucidation
of mescaline and the preparation of N-methyl and
N-acetyl derivatives of mescaline has
served to strengthen this concept and to broaden the
scope of permissible derivatives (Spath 1919). In the
ensuing years much knowledge has been gained
regarding biologically useful derivatives of the naturally
occurring drugs but, most importantly, the
structures of the alkaloids and the protoalkaloids
have, one by one, been elucidated. This knowledge
has then allowed researchers of recent times to deduce
many of the structure relationships associated with
specific biological responses. The sum of this hardwon
nowledge allows one to produce pharmaceutically
useful compounds, which have no counterpart
in nature, from off the shelf chemicals. Unfortunately
there are those people who would take this
body of knowledge and, rather than use it for the
enhancement of medical science, use it for their own
financial gain. Individuals such as these have created
the so-called designer drug phenomenon.
Henderson (1986) first described a synthetic
drug as one which was designed by a clandestine
chemist to produce a certain pharmacological
response. However, today designer drugs are universally
understood to belong to a group of clandestinely
produced drugs which are structurally and pharmacologically
very similar to a controlled substance but
are not themselves controlled substances (Langston
and Rosner 1986). The Drug Enforcement Administration
(DEA) has noted that the designer drug
terminology tends to cast a somewhat glamorous aura
onto the concept, and as a result, the DEA feels that
it would be wise to refer to these compounds in some
other manner and suggests the use of the term
Controlled Substance Analogs (CsA).
In October of 1987 the United States Government
amended the Controlled Substance Act in an effort to
curtail the illicit introduction of new CsA's.
amendment states that any new drug which is substantially
similar to a controlled substance currently listed
of Federal Regulations (CFR), Schedule
I or II, and has either pharmacological properties
similar to a Schedule I or II substance or is represented
as having those properties, shall also be considered a
controlled substance and will be placed in Schedule I.
The amendment further contains provisions which
exempt the legitimate researcher as well as compounds
that are already being legally marketed from the provisions
of the amendment.
Since the CsA amendment has yet to be tested in
a court of law, it is much too early to say how
successful it will be in limiting the spread of the CsA
phenomena. However, it is safe to assume that there
will be those who believe that they can manage to
evade the provisions of the CsA amendment, and
much of the world has not yet even attempted to find
a litigious solution to the problem of CsA's. Therefore,
an attempt to identify those CsA's which would
be logical candidates for synthesis by a clandestine
chemist is still a pertinent exercise.
A great many compounds, when taken in sufficient
quantity, will alter one's perception of reality.
For the purposes of this paper, the term hallucinogen
is reserved for those compounds that are characterized
by the predominance of their actions on mental
and psychic functions (Brown 1972).
Hallucinogens can be classified according to
structural similarities into four groups of compounds
and into one group containing miscellaneous structures.
The classifications are: indoles, phenylalkylamines,
piperidyl benzilate esters, cannabinoids and
The piperidyl benzilate esters have been extensively
studied and relationships between psychotomimetic
activity and chemical structure have been
established (Abood et al. 1959; Abood and Biel
1968). The N-methyl and N-ethyl-3-piperidyl benzilate
esters are controlled substances and are listed
under the CFR Schedule I as hallucinogens. Benactyzine
is a noncontrolled drug which is used medically
as an antagonist to cholinergic nerve fibers (Biel et al.
1962). It appears that the pharmacological effects of
the piperidyl benzilate esters may not be conducive to
a good trip for the user. Brown describes the pharmacological
effects by explaining how thought processes
are severely disrupted. He reports that speech is
disorganized and incoherent, and that confusion,
disorientation, and amnesia occur often and may be
long lasting (Brown 1972). Perhaps these compounds
should not be classified as hallucinogens but rather as
incapacitating agents. Additionally, although the
pharmacological effects of the piperidyl benzilates
have been compared to those elicited by phencyclidine
(Shulgin 1969), there is no evidence to suggest any
significant abuse of these compounds. Therefore, no
further discussion will be given to the piperidylbenzilate esters.
Given the world wide ready availability of marijuana,
it is somewhat difficult to produce a viable
argument for making CsA's of cannabinoids. However,
ten years ago (1978) an attempt to produce
CsA's from cannabis extracts was encountered in the
Jacksonville, Florida area. In this case a concentrated
extract of cannabis had been obtained by a soxhlet
extraction. The extract had been acetylated with
acetic anhydride, and in the final step, the excess
acetic anhydride removed by distillation (reference is
unretrievable due to its appearance in an underground
periodical). The product contained neither quantities
of nonderivatized cannabinoid nor any identifiable
plant fragments. Since this single instance, no acetalaced
cannabinoid samples have been reported by a
DEA laboratory. Therefore, this instance is assumed
to represent an isolated occurrence and as such, will
serve to terminate our discussion of cannabinoid
Under the heading miscellaneous, one must
include nearly any ingestible compound known to
man, as any substance taken at toxic levels will alter
one's perception of reality. Obviously a discussion of
all such compounds as models for CsA hallucinogens
is not within the scope of this article. However, the
compound known as phencyclidine (PCP or
N-(1-phenylcyclohexyl)piperidine), although developed by
Parke Davis and Company (Rochester, Michigan) as
an anesthetic, does produce psychotomimetic effects
and is widely abused in the United States. It is listed
in the CFR under Schedule II, and two of its
homologs and one analog are listed under Schedule I.
Therefore, in the following discussions, the
PCP will be
considered as possible candidates for hallucinogenic
The literature covering indole chemistry is huge
and diverse. Over 500 naturally occurring indole
alkaloids were known by 1972 and accounted for
nearly one fourth of all alkaloids known at that time
(Robinson 1968). By 1980, the number of known
indole alkaloids had risen to approximately 1200
(Kisakurek and Hesse 1980). Today there have been
many more indoles added to the list of naturally
occurring alkaloids. These alkaloids include such
pharmacologically and structurally diverse compounds
as tryptophan (essential amino acid), reserpine
(tranquilizer), strychnine (stimulant-convulsant), harmaline
(hallucinogen), serotonin (anticholinesterase-monoamine oxidase
inhibitor), ergometrine (oxytocic),
vinblastine (antitumor agent), and psilocybin (hallucinogen).
Only nine compounds containing the indole
nucleus are controlled substances under the United
States Federal Statutes. Three of these compounds are
classified as ergot alkaloids, five are simple
3-(2-ethylamino)indoles, and one is the pentacyclic alkaloid,
ibogaine. The ergot alkaloids are lysergic acid,
lysergic acid amide, and lysergic acid diethylamide
(LSD). The five controlled indolealkylamines are
N,N-dimethyltryptamine (DMT), N,N-diethyltryptamine
(psilocin), and the phosphate ester of
Because the major pharmacological effects of
ibogaine are probably not those of a hallucinogen
(Schneider and Siggs 1957; Turner et al. 1955; Wooley
1962) and because only a very few illicit samples have
been encountered, we will not discuss the subject
Lysergic acid (compound 1, Figure 1) is a tetracyclic
compound, and as noted previously, contains
an indole nucleus and belongs to the family of ergot
alkaloids. Nearly all of the known naturally occurring
hallucinogens have a 3-(2-ethylamino)indole
contained within the molecular structure.
The assessment of a particular LSD derivative as
a candidate for a future CsA involves the consideration
of several points. The most important are those
attempts made by other researchers to modify the
structure of LSD while retaining hallucinogenic activity.
To date, all attempts to modify the tetracyclic ring
system have resulted in a loss of hallucinogenic
activity. For instance, of the four possible C-8 stereoisomers
only the dextro isomer of LSD is hallucinogenic
(Rothlin 1957a). Modification of the amide
alkyl substituents also reduces hallucinogenic activity
substantially (Usdin and Efron 1972). Additionally,
substitution with either a hydroxyl or a methoxy at
the C-12 of LSD results in a compound with no
hallucinogenic activity (Usdin and Efron 1972),
whereas a comparably substituted methoxyindolealkylamine
appears to always be hallucinogenic
(Gessner and Page 1962). The only structural modification
which results in the maintenance of hallucinogenic
activity on par with LSD is the substitution
of either a methyl or an acetyl to the indole nitrogen
The total synthesis of LSD derivatives is not
simple and requires the talents of an adept synthetic
chemist (Jacobs and Craig 1934; Kornfeld et al. 1954;
Garbrecht 1959). Much of the LSD produced today
uses ergotamine that is obtained from legitimate
commercial sources (Golden, L. personal communication).
However, if ergotamine becomes difficult to
obtain from commercial sources, the ergot alkaloids
can be produced easily and in large quantities by
cultivating strains of the fungus Claviceps in submerged
cultures (Spalla 1980). Given the fact that
structural modifications of the tetracyclic ring system
are likely to result in a product with either little or no
activity, and the fact that there will never be a
shortage of ergot alkaloids for clandestine syntheses,
it is quite unlikely that the total synthesis of LSD or
derivatives thereof will become commonplace in the
near term. One final point to consider is that the CFR
lists LSD and all optical, geometrical, and positional
isomers of LSD under Schedule I, and Iysergic acid
and lysergic acid amide under Schedule III.
Because of previously noted pharmacodynamics
and the imposing nature of a total synthesis, the
immediate precursor of a LSD derivative synthesis
will most certainly be a controlled substance, namely
Iysergic acid; therefore, much of the impetus for
producing noncontrolled LSD derivatives is lost.
However, if the CsA amendment were not a consideration
there would be a clear first choice via substitution of
the indole nitrogen to create either 1-alkyl
or 1-acyl derivatives. Derivatives of this type most
probably fall under the purview of the CsA amendment.
The N,N-methylpropyl isomer of LSD has
been the only derivative of LSD examined by the
author. Derivatives of this type might seem to be an
unlikely choice for a CsA due to a high probability of
significant loss in hallucinogenic activity. However, a
reduction in hallucinogenic activity may become
acceptable to the U. S. clandestine chemist when he
notes that lysergic acid amide is listed as a Schedule
III substance in the CFR; therefore, structurally
similar substances of this compound are exempted
from the CsA amendment. A lucid argument can
then be made that lysergic acid N,N-dimethylamide is
derived from lysergic acid amide rather than LSD.
Carrying this theme to the next logical step one would
then assume that the 1-alkyl and 1-acyl derivatives of
the N,N-dimethyl isomer would also not be controlled
by the CsA amendment. At present, no known
CsA of LSD has ever been encountered by the DEA.
All of the hallucinogenic indolealkylamines can
be classified as belonging to the family of compounds
known as tryptamines and are substituted 3-(2-ethylamino)indoles
(compound 2, Figure 2).
The tryptamines are a most interesting and biologically
useful class of compounds. In the human
body, serotonin (5-hydroxytryptamine) functions as a
vasoconstrictor, inhibits gastric secretion, stimulates
smooth muscle, and is naturally present in the central
nervous system where it is involved in neurotransmission
(Goodman and Gilman 1970). The 5-methoxy
homolog of serotonin is considered to be hallucinogenic
in humans as is the 5-methoxy homolog of gramine
(3-(N,N-dimethylaminomethyl)indole) (Gessner et al.
1961). Melatonin (N-acetyl-5-methoxytryptamine),
formed by the mammalian pineal gland, appears to
depress gonadal function and is known to cause contractions
of melanophores. Bufotenine, the N,N-dimethyl
homolog of serotonin, is classified as a very
weakly active hallucinogen and is noted to have
extremely unpleasant cardiovascular depressive side
effects (Holmstedt et al. 1967). The O-methyl homolog
of bufotenine, N,N-dimethyl-5-methoxytryptamine (5-methoxy-DMT),
is reported to be an extremely potent
hallucinogen, but it, like all other C-5 substituted
indolealkylamines, is not active if taken by mouth
(Brown 1972). Both DMT and DET are well known for
their hallucinogenic activity, just as both of these compounds
are also inactive if taken by mouth. The N,N-dipropyl
and diallyl derivatives are also hallucinogenic
only if used either parenterally or by inhalation at
approximately the same level as DET, whereas higher
homologs abruptly become inactive (Szara and Hearst
1962). The compound 6-hydroxy-DET has been determined
to be a major metabolite of DET in man (Szara
et al. 1966), and it does not possess hallucinogenic
activity (Szara 1970). Conversely, the 4-hydroxy-N,N-dimethyltryptamines
(psilocin and psilocybin), are very
active hallucinogens when taken orally. The activity of
psilocybin (O-phosphoryl-4-hydroxy-DMT) when taken
by mouth is not related lo the phosphoric acid radical
since the pharmacological effects of psilocin (4-hydroxy-DMT)
are identical (Horita and Weber 1961).
Pharmacological information for baeocystin (4-hydroxy-N-methyltryptamine)
was not found; however,
one would expect hallucinogenic activity to parallel that
of the N-alkyl-tryptamines and thereby would expect
the drug to be weakly hallucinogenic.
It is thought that in the past most clandestine
syntheses of indolealkylamines used indole as the starting
material (Speeter and Anthony 1954). A modest
literature search will convince a clandestine chemist that
the use of the Fischer indole synthesis affords access to
a greater variety of indole derivatives (Huisgen and Lux
1960; Robinson 1983) as it will also reduce the chance
that law enforcement will be alerted by his purchases of
essential chemicals. Hence, in the production of
indolealkylamine derivatives, the covert chemist need
not be limited by the commercial availability of appropriate
Relative to those which lack an aryl ring
substitution, there is no doubt that the activity of
psilocybin/psilocin upon ingestion is due to an
enhancement of gastrointestinal absorption which, in
turn, must be structurally related to the presence of
the C-4 hydroxyl substitution. Therefore, if the CsA
amendment were not a consideration, derivatives
derived from psilocin would be the obvious first
choice. These derivatives are the 4-hydroxy-N,N-alkyl
homologs starting with N,N-dimethyl, N,N-methyl-ethyl,
and on to N,N-diallyl to give a total of 10
possible derivatives. As is also the case for hallucinogenic
phenylalkylamines, alkyl substitution, not to
exceed a C-3 moiety, at the position alpha to the side
chain nitrogen generally will maintain hallucinogenic
activity. This brings the total possible number of
hallucinogenic CsA's of psilocin to 40. A somewhat
removed second choice would be the same series of
derivatives in conjunction with either acetylation or
methylation of the indole nitrogen. This would then
bring the total number of the possible 4-hydroxy
substituted tryptamine CsA's (less one for psilocin) to
The 5-methoxy derivatives of gramine and serotonin
are first choices for future CsA's when considering
the new U. S. amendment. Substitution at the
alpha carbon on the side chain will probably maintain
psychotropic activity only for serotonin derivatives.
Hence, allowing only a methoxy substituent at the
aryl C-5 position, and a substitution at the carbon
alpha to the nitrogen (the nitrogen being any combination
of hydrogen, methyl, ethyl, n-propyl, and
allyl) 75 CsA's can be obtained. Then substitution of
the indole nitrogen with either methyl or acetyl brings
the total number of possible CsA's that can be
argumentatively related to serotonin to 225.
An additional series of compounds that could
serve as future CsA's under U. S. law are those which
are substituted with alkyl groups at the carbon alpha
to the side chain nitrogen. Recently, a commercially
available tryptamine which has an ethyl moiety substituted
at the alpha carbon has become the newest
U.S. tryptamine CsA. Known as ET in the illicit CsA
drug market is 3-(2-amino-butyl)indole (etryptamine,
monase by Upjohn (Kalamazoo, MI); compound 3,
Figure 3). Because ET does not appear in either
Schedule I or II of the CFR and is a legally marketed
product, ET and derivatives thereof are exempted
from control under the CsA amendment. Pharmacokenitic
data on ET indicates that it is a monoamine
oxidase inhibitor (Govier et al. 1953; Klein and Davis
1969) and psycho-energizer (Robie 1961; deHaen
1964). Hence, ET could produce some degree of
hallucinogenic activity in man. In 1986 ET was
reported as the she causative agent in a fatal overdose in
Duesseldorf, Germany (Daldrup et al. 1986). This
may be one of the few times that a CsA has originated
outside of the U. S. The sample of ET which was
submitted to our laboratory appears to have been
obtained from the Aldrich Chemical Company
($48.05/100 gm; Milwaukee, WI). Unfortunately, it is
not yet clear if ET is actually the substance which is
producing the biological response being sought by the
illicit user. It is the case that the sample of ET we
examined and the batch of ET which the Aldrich
Chemical Company is presently selling contains a
major quantity (about 30%) of the agent shown in
Figure 4 which could also be a hallucinogen (Turner
1963; Naranjo 1967).
Nomenclature for this possible hallucinogen
can either be 1-methyl-3-ethyl-1,2,3,4-tetrahydro-harmane,
The creation of this substance most
probably occurred after synthesis and during the
purification of ET. Under anhydrous conditions, the
reaction of acetone and ET would give the correponding
enamine which could then undergo a Mannich
condensation to yield the hallucinogen (Whaley
and Govindachari 1951; Shoemaker et al. 1979). The
(harmaline) is considered to be a hallucinogen (Hochstein
and Paradies 1957) as well as a monoamine oxidase
inhibitor (Burger and Nara 1965). On
the other hand, the compound 2-methyl-8-methoxy-2,3
4,5-tetrahydro-[beta]-carboline is classified as a
tranquilizer (Usdin and Efron 1972). We were not
able to attain any literature whatsoever on the hallucinogen
shown in compound 4 (Figure 3), much less
any pharmacokenetic data. Hence, due to the apparently
unpredictable pharmacological behavior of
structurally similar [beta]-carboline derivatives, I will
not speculate as to the pharmacological properties of
As was observed for the simple indole alkaloids,
there are several simple phenylalkylamines which play
important roles in the normal biological function.
Some of these are tyrosine, 3,4-dihydroxyphenylalanine
(DOPA), 3,4-dihydroxytryptamine (dopamine),
and norepinephrine. The naturally occurring hallucinogenic
protoalkaloid, mescaline, is 2-(3,4,5-trimethoxyphenyl)ethylamine.
which impart hallucinogenic activity to phenylethylamines have
een studied and a considerable quantity of that data is
easily retrieved. The following
constitutes a brief review of some of the most salient
concepts relative to hallucinogenic activity chemical
structure relationships within the family of phenylethylamine derivatives.
It has been found that the addition of methoxy
moieties to the aromatic ring of a phenylethylamine,
in general, produces compounds that are psychotomimetic
(Shulgin et al. 1969). Further, it has been
noted that the methylenedioxy moiety can be used in
the place of two adjacent ring substituted methoxy
groups with C-3,4 substitution providing the most
potent psychotogens (Alles 1959; Shulgin 1964;
Naranjo et al. 1967; Braun et al. 1980a). Historically
3,4-methylenedioxyamphetamine (MDA) has probably
been the most consistently abused psychotomimetic
phenylethylamine. Amphetamine and methamphetamine are
adrenomimetic at low to moderate
dose levels; however, at high dose levels they also
become psychotomimetic in man (Liddel and Weil-Malherbe
1953; Connell 1958). Additionally, it has
been found that the addition of an [alpha]-alkyl
moiety (up to C-3) (Snyder and Richelson 1970) to
methoxyphenylethylamines results in an increase in
hallucinogenic activity and, alkyl only substitutions
to the aromatic ring tend to result in a gradual loss of
central activity which can be related to the increasing
size or the alkyl group (Marsh and Herring 1950;
Harris and Worley 1957). Braun et al. (1980b) has
determined that a gradual decrease in psychotomimetic
activity also occurs with the increasing size of a
N-alkyl substituent. Braun also noted that upon
N,N-dialkyl substitution an abrupt and significant
loss of hallucinogenic activity occurs, whereas N-hydroxy
substitution maintains activity.
The bases of structure-activity relationships as
determined by aromatic ring substitutions are not
obvious. For instance, mescaline has relatively prominent
psychotomimetic properties but 3,4-dimethoxyphenylethylamine
(3,4-dimethoxydopamine) is not
considered to be psychotogenic, and the hallucinogenic
potency of 3,4-dimethoxyamphetamine is less
than that of mescaline (Hollister and Friedhoff
1966). On the other hand, the hallucinogenic potency
of 3,4-methylenedioxyamphetamine is approximately
three times that of mescaline (Braun et al. 1980b).
Also, tyramine (4-hydroxyphenylethylamine) is
devoid of hallucinogenic activity, but 4-methoxy-tyramine
is weakly hallucinogenic (Smythies et al.
1969). However, 2-methoxymethamphetamine has no
known hallucinogenic activity (Usdin and Efron
1972), and the 4-methoxyphenyl-[alpha]-methylethylamine
(4-methoxyamphetamine) has five limes the
psychotropic activity of mescaline (Shulgin 1970). To
complicate the situation further, one work reported
the synthesis of 4-substituted methamphetamine
derivatives using both ring activating and ring deactivating
substituents of quite different atomic volumes, and found
hallucinogenic activity present for
all derivatives. The compounds in question are 4-bromo-,
4-amino-, 4-chloro-, 4-nitro-, 4-iodo-, and
4-hydroxymethamphetamine (Knoll et al. 1966). It is
a little surprising that substituents of such radically
different atomic volumes and electronegativities
would all give 4-substituted- phenylisopropylamine
derivatives having psychotropic activity. In contrast,
another study of hallucinogenic activity as a function
of aromatic ring substitution, found the compound
2,5-dimethoxy-4-methylamphetamine to be some
eighty times more potent than mescaline but upon
going to the 4-ethyl derivative, quite a trivial change,
nearly all hallucinogenic activity was supposedly lost
(Shulgin 1969). Despite these seeming inconsistencies,
many of the necessary structural requirements
for producing hallucinogenic phenylethylamine can
be understood by noting the common structural features of
these psychotogens. The structure activity
relationships noted above can be found in a single
source review article by Shulgin (1970).
The following phenylalkylamines are listed
under Schedule I of the CFR as hallucinogens:
The majority of the hallucinogenic phenylethylamines
which are presently controlled under U. S.
law were first encountered in a relatively short period
of time in the latter part of 1960. Since that time the
emergence of new CsA's of psychotogenic phenylethylamines
has continued but at a much reduced pace.
Starting in 1972, several samples of MDMA were
analyzed by DEA laboratories. Apparently MDMA
was readily accepted by the user and abuse has
continued to increase. Presently in the U. S. and
Canada there are at least four other CsA's of psychotogenic
phenylethylamines in the illicit market.
These are N-hydroxy-3,4-methylenedioxyamphetamine
(N-hydroxy MDA), N-ethyl MDA (EVE,
MDEA), 4-ethoxy-2,5-dimethoxyamphetamine (MEM)
(Avdovich et al. 1987), and 4-bromo-2,5-dimethoxyphenylethylamine
(DBMPEA) (Sapienza, E personal communication; Allen, A.
personal communication). Upon
placing MDMA under legal controls, the N-ethyl
homolog of MDA (EVE) was immediately introduced
as a replacement for MDMA. However, it seems that
EVE has not been well accepted by the user, apparently
because EVE has a lower potency than MDMA; therefore requiring
a larger dose to produce psychotropic
effects and often resulting in making the user ill (Jordan
- 4-bromo-2,5-dimethoxyamphetamine (DOB)
- 2,5-dimethoxyamphetamine (DMA)
- 4-methoxyamphetamine (PMA)
- 5-methoxy-3,4-methylenedioxyamphetamine (MMDA)
- 4-methyl-2,5-dimethoxyamphetamine (DOM, STP)
- 3,4-methylenedioxymethamphetamine (MDMA, ecstasy)
- 3,4,5-trimethoxyamphetamine (TMA)
- 2-(3,4,5-trimethoxyphenyl)ethylamine (mescaline)
Assuming the ready availability of the appropriate chemical
precursors, and assuming a lack of
concern for the legal provisions enacted by governments
for the purpose of controlling CsA's, choices
for CsA's of ring substituted phenylethylamine psychotogens
are numerous. Previously cited literature
provides many such CsA possibilities with at least ten
aromatic ring substituted amphetamines (compounds
numbered 5-15, Figure 4) having potencies greater
than mescaline (compound 5). Other CsA's can be
obtained from compounds 6 through 15 by modification
of the [alpha]-alkyl side chain to either C-2 or
C-3 alkyls, and mono-substitution or the nitrogen
with either hydroxy or short chain alkyl. These
modifications result in a total Of 160 possible CsA's
based only upon the ring substitutions of the aforementioned
compounds. Additionally, tile ring substituted
phenylisopropylamines which are presently
controlled substances, can be modified in the same
manner, and after excluding controlled substances
and N-hydroxy MDA, there are 118 more possible
derivatives, giving a total of 278 possible new CsA's.
Each time a new ring substitution is introduced, such
as MEM, then this number is increased by 16.
If the U. S. CsA amendment is a consideration,
then psychotomimetic phenylethylamines could be created
from compounds which are structurally related to dopamine,
and norepinephrine (3,4-di-hydroxyphenyl-[beta]-hydroxyethylamine).
A case in point is the compound macromerine,
known psychotogen (Hodgkins et al. 1967). Some
other compounds which could be used as CsA models
are synephrine (N-methyl-4,[beta]-dihydroxyphenylethylamine),
phenelzine (phenylethylhydrazine), and tranylcypromine
modifications of these compounds could provide
quite a few additional CsA's. Because of the sheer
size of the task, no attempt was made to determine
the total number of possible CsA's that could be
derived by using these compounds as models. How
ever, the magnitude of the possibilities become evident
when one calculates tile possible CsA's which,
could be obtained using just dopamine (compound
16, Figure 5) as the model compound, as is demonstrated
in the following paragraph.
The total number of possible CsA's were limited
by the following considerations:
Given these considerations there are 47 structures
which can be drawn. Each one of these can then exist
as 16 derivatives obtained by substitution as shown
above at the alpha carbon and nitrogen. The multiplication
product of these two values provides the
total number of possible hallucinogenic CsA's (752)
which, one could argue, are structurally related to
- ring substitution at C-3,4 is dimethoxy
- ring substitution to sites C-2,5,6 were limited to
combinations of CH3-, Br-, Cl-, and CH3-,
- substitution on the amine nitrogen and the alpha
carbon were limited to the following:
- of the three ring sites available for substitution,
no more than two were allowed for any given structure
- single substitution on the ring at C-2 to give
2,3,4-trisubstituted derivatives was disallowed
- mixed halide structures were excluded
- ring substitutions which would result in any derivative which
is presently a controlled substance were disallowed.
Research targeted at the determination of
structure-psychotropic activity relationships has waned in
recent years. Perhaps in future years it will be the
clandestine chemist who will fill in the blanks.
The synthesis of phencyclidine (PCP) was first
reported in 1958 (Chen 1958) and patent rights were
granted to Parke, Davis & Co. in 1960 and 1963 for
medical use as an anesthetic (Parke, Davis & Co.
1960; 1963). PCP first came to the attention of DEA,
then the Bureau of Narcotics and Dangerous Drugs,
as a drug of abuse in the latter part of the 1960's.
Pharmacologically, PCP has been described as a
pseudo hallucinogen which has many of the characteristics
of a depressant drug (McGlothlin 1971).
Without question, PCP deserves a special niche in
any discussion of drugs of abuse if for no other
reason than the notoriously bizarre effects it has been
known to have upon some of the abusing population
(Peterson and Stillman 1978).
The now so very familiar synthesis using
1-(1-piperidyl)cyclo-hexyl carbonitrile and phenyl Grignard
reagent was published by Maddox et al. in 1965
and, either fortunately or unfortunately depending
upon one's point of view, the accompanying pharmacological
data was useless as it could not be correlated
to the compounds synthesized (Maddox et al. 1965).
However, pertinent literature is not hard to find as
both the original U. S. patent (Godefroi et al. 1963)
and later studies have provided a pharmacological
basis for the production of CsA's of PCP (Kalir and
Pelah 1967; Kalir et al. 1969).
It does not appear to be possible for one to
generate a CsA model structure that will not fail
under the CsA amendment provision which stipulates
that the term "controlled substance analogue" means
a substance-the chemical structure of which is substantially
similar to the chemical structure of, in this
case, PCP. This is the result of the fact that a one
carbon separation between an aryl system and the
amine nitrogen, and the fact that the central carbon
between these moieties is in a ring system appear to be
principal requirements for PCP-like pharmacological
activity. Other activity structure relationships are:
Because of factors noted above, there appears to
be a relatively small probability of a PCP CsA
appearing in the illicit marketplace that will not fall
under the purview of the U. S. CsA amendment.
However, it is also the case that under U. S. law there
is a reporting requirement placed upon the purveyors
of piperidine. Since the implementation of the piperidine
reporting requirement it has become much
more difficult for the clandestine chemist to safely
acquire this chemical precursor of PCP. Therefore, a
market force has been introduced that will almost
certainly result in the production of PCP CsA's
which will not contain a simple piperidino moiety.
This thought, taken with the previously discussed
activity-structure relationships, allows one to suggest
the 50 structures depicted in Figure 6 as being representative
of future CsA's of PCP. Of these 50 compounds,
two have already been placedin the CFR
Schedule I: N,N-(1-phenylcyclohexyl)-ethylamine
- substituents which decrease lipophilic
character generally decrease potency
- aryl substitution with 2-thienyl generally
- substitutions onto the aryl system
- to maintain potency N,N-dialkyl substitutions should be
either piperidino or pyrrolidino ring systems
- N-ethyl is the most potent N-alkyl monosubstitution and
potency falls off rapidly with either an increase or decrease in the
alkyl chain size
- substitution on the beta carbon of either
the cycloalkyl or the cycloalkylamino rings
will most likely be synthetically difficult due
to steric considerations.
Relative to medical usage, a stimulant is defined
to be an agent that arouses organic activity, strengthens
the action of the heart, increases vitality, and
promotes a sense of well being. However, as per the
medical definition, the effects produced by a stimulant
may not be a very accurate term for the effects
sought by those who abuse these compounds. For
instance, at dose levels usually equated with heavy
abuse, both amphetamine (Hampton 1961; Angrist et
al. 1969) and methamphetamine (Liddel and Weil-Malherbe
1953) are thought to be psychotogenic.
Therefore, several of the amphetamines could be
discussed as hallucinogens; however, it seems most
likely that a substantial portion of the abuse of
stimulant drugs is performed with the intention of
inducing a state of euphoria (Brown 1972). Historically,
the abuse of stimulants (euphoriants) has been
largely confined to amphetamine, derivatives thereof,
and cocaine. Some of the amphetamine derivatives
which have been controlled under U. S. law are
methamphetamine, N-ethylamphetamine, fenethylline,
phenmetrazine (preludin), phendimetrazine,
benzphetamine, chlorphentermine, clortermine,
diethylpropion, methylphenidate, pemoline, and
amphetamine. Other derivatives of amphetamine
which have been encountered in samples submitted to
DEA laboratories, but have not yet been brought
under legal controls, are bis-methamphetamine (compound 18,
Figure 7), fencamfamine (compound 19,
Figure 7) (Nied and Smith 1982), N,N-dimethylamphetamine
(dimephenopan; compound 20, Figure 7)
(Allen, A. personal communication), and an analog
of pemoline, 4-methylaminorex (U4EUH) (compound 21,
Figure 7) (Inaba and Brewer 1987). Since
pemoline is listed under Schedule IV of the CFR and
4-methylaminorex is clearly an analog Of pemoline, it
falls outside of the guide-lines set forth in the CsA
amendment; therefore, 4-methylaminorex is not controlled
under U. S. law. It is equally clear that
bis-methamphetamine and N,N-dimethylamphetamine do
fall under the CsA guidelines and would be
considered controlled substances under tile CsA
amendment. However, it may be that N,N-dimethylamphetamine
may not enjoy a long history in the
clandestine market as at least one work states that it
is considerably less potent than methamphetamine
(Schaeffer et al. 1975).
Most of the adrenomimetic activity-structure
relationships were delineated in the previous discussion
on psychotomimetic phenylethylamines. The
principle difference between the pharmacological
action, as related to structure for these two classes of
compounds, is determined- by the nature of the
substituents on the aryl system. In general it is noted
that substituents on the aryl system which are orthopara
directors tend to produce psychotogenic compounds
with methoxy substituents often producing
the most pharmacologically active hallucinogens.
However, there are several exceptions to this general
statement, not the least of which is exemplified by
substitution on the phenyl ring of the electrophilic
hydroxy moiety which in nearly every case either
eliminates or greatly reduces hallucinogenic activity.
On the other hand, adrenomimetic activity is clearly
enhanced by branching of phenylethylamine at the
carbon alpha to the amine nitrogen and is maintained
at reasonable levels by substitution to the nitrogen as
shown in table II. Both N-ethylamphetamine and
N,N-dimethylamphetamine have appeared in the
illicit market and clearly follow the points made
above. However, a market factor has been introduced
by the fact that phenyl-2-propanone (P2P) has been
listed under the CFR as a Schedule II substance.
Hence, it makes little sense for the clandestine chemist
to produce CsA's of phenylethylamines which
have potencies that are less than methamphetamine if
he is going to produce his CsA's in a synthesis that
uses P2P. The recent illicit use of 4-methylaminorex
may well be the result of the clandestine chemist
trying to circumvent the legal problems associated
with P2P. On the other hand, the sum total of
methamphetamine still being covertly produced suggests
that the control of P2P has not appreciably
reduced the drug's availability in the illicit marketplace.
As before, if the chemist is not concerned about
the CsA amendment, the structural possibilities
offered by Table II, less the three controlled substances
that are included, provides for thirteen possible
future stimulant CsA's. It would seem that the
single most logical next stimulant CsA would be
N-methyl-[alpha]-ethylphenylethylamine. This compound
should be pharmacologically very similar to
methamphetamine and synthesis could employ
1-phenyl-2-butanone instead of P2P. Alternatively, the
use of 1-(4-fluorophenyl)propan-2-one, in place of
P2P, would almost certainly give a product with
adrenomimetic properties, and may in fact be considerably
more potent than methamphetamine.
The clandestine chemist of limited chemical
sophistication may not notice the structural similarity
of such compounds as methylphenidate (compound
22, Figure 8), phenmetrazine (compound 23, Figure
8), 4-methylaminorex (compound 21), and amphetamine
(compound 24, Figure 8). If he does recognize
the constancy of the phenylisopropylamine substructure
in these compounds he may well explore the
literature in an effort to determine the structural outer
limits for the phenylisopropylamine stimulants. At
what may be near these structural outer limits he will
find a class of compounds which are correctly
referred to as conformationally rigid phenylethylamines.
Some of the conformationally rigid phenylethylamines are
fencamfamine (compound 19),
tranylcypromine (2-phenylcyclopropylamine) (compound
5, Figure 9), 2-phenyl-cyclohexylamine (compound
26, Figure 9) (Smissman and Pazdernik 1973),
2-amino-3- phenyl-trans-decalin (compound 27, Figure
9), and 2-aminotetralin (compound 28, Figure 9)
(Barfknecht et al. 1973). The potency of most of
these compounds is highly dependent upon stereochemistry.
Those isomeric forms which most closely
approximate the anti periplanar conformation
observed for amphetamine in solution are the most
potent stimulants. Hence, transtranylcypromine is
considerably more potent than is the cis isomer
(Grunewald et al. 1976). The most active isomer of
these compounds does not approach the potency of
the simple phenylisopropylamines. Given this reduction
in potency for the most active isomers one would
think that, in order to obtain amiable product for the
illicit market, a stereo specific synthesis would be
required. This feature, along with a lowered potency
for even the more active isomers, may very well
exclude the conformationally rigid phenylethylamines
from the synthetic repertoire of the surreptitious
chemist. Hence, it is a reasonable expectation that
those conformationally rigid phenylethylamines
which will be abused in the future will be obtained by
diversion of limit supplies rather than by clandestine
Unfortunately, it seems to be an axiom that any
compound which has any possibility of altering
man's perception of himself or his surroundings will
at some time be abused. Propylhexadrine, although
not an extreme example, is nevertheless an example of
a compound which has been abused although adrenogenic
potency is far less than that of methamphetamine
(Garriott 1975). Therefore, one must expect
some abuse of the conformationally rigid phenylethylamines to
occur. It would be my guess however, that
the extent of such abuse will never be large.
The parent structure for 4-methylaminorex has
been known since 1889 (Gabriel 1889) and many
derivatives thereof have been studied for pharmacological
activity. Pemoline (2-amino-5-phenyl-2-oxazolin-4-one)
(Traube and Ascher 1913; Howell et al. 192) is presently a
controlled substance in the U. S.,
is classified as a stimulant, and is listed under Schedule
IV of the CFR. Poos (personal communication)
synthesized and performend pharmacological studies
for some twenty seven 2-amino-2-oxazoline isomers
of which aminorex and 4-methylaminorex were two.
In this work, aminorex and 4-methylaminorex,
regardless of the steroisomer employed, were found
to have anorectic activity on par with d-amphetamine.
However, adrenomimetic activity of 4-methylaminorex
was determined to be less than that of
amphetamine and similar to phenmetrazine (Patil and
Yamauchi 1970). It has been suggested that the
effectiveness of stimulant drugs as appetite suppressants
are the result of the fact that the user forgets to
eat and that this behavior is in direct proportion to
the adrenomimetic activity of the drug (Cutting
1969). Contrary to previously cited work this suggests
that aminorex may in fact be as potent an adrenomimetic
as amphetamine. In any case, Poos (personal
communication) highlighted eight compounds which
may have adrenomimetic activity similar to those of
amphetamine and methamphetamine. Shown in Figure
10 and listed in decreasing order of anoretic
activity they are compounds:
33) 2-amino-5-phenyl)-2-oxazoline [aminorex]
36) 2-amino-4-methyl-5-phenyl-2-oxazoline [4-methylaminorex]
Although not mentioned in this work, one would
immediately assume that the 4-fluoro- and 4-chloro-
phenyl derivatives of compounds 35 and 36 would
also have significant anoretic activity.
Given the astoundingly simple synthetic process
required to produce these compounds, and the fact
that the 4-halogen substituted aryl derivatives would
require precursors unlikely to titillate the interest of
law enforcement agencies, these compounds will
most probably be made in future clandestine syntheses.
It is also conceivable that some enterprising
clandestine chemist will wonder if appropriately substituted
methoxy derivatives will have psychotomimetic properties.
The literature contain many references to stimulant
drugs of variant structures which may not spark the
interest of the less knowledgeable clandestine chemist.
However, nearly all of these compounds can be accessed
through literature searches for either derivatives of
phenylethlamines or stimulant compounds. Several
compounds which serve as examples are fenmetramid
(Ippen 1968), prolintane, 1-([alpha]-propylphenylethyl) pyrrolidine
(Heinzelman et al. 1960; Hollister and
Gillespie 1970), pyrovalerone
(1-(4-methylphenyl)-1-oxo-2-pyrrolidino-n-pentane) (Heinemann and Vetter
1965; Heinemann and Lukacs 1965),
N,3,3-trimethyl-1-(m-tolyl)-1-phthalanpropylamine (compound 37,
Figure 11)(Gill et al. 1970), zylofuramine
([alpha]-benzyl-n-ethyltetrahydro-D-threo-furfurylamine) (Harris et al.
1963), a series of N-substituted phentermine compounds
(Borella et al. 1970), 4-hydroxyamphetamine
(Mannich and Jacobsohn 1910; Hoover and Hass
1947a,b), N-methylephedrine (Smith 1927), nylidrin,
(Treptow et al. 1963),
pheniprazine, [alpha]-methyl-phenylethyl hydrazine
(Zbinden et al. 1960), and N,N-diethyl-2-phenylcyclopropylamine
(SKF). All of these compounds are derivatives of
phenylethylamine with the exception of
compound 37 which is a 3-phenyl-3-propylamine substituted
onto a phthalane at C-1. A number of closely
allied derivatives of this compound have been examined
and are classified as weak stimulants.
Fenmetramide is noteworthy in that it is a 2-one
derivative of phenmetrazine. Any and all of these
compounds are subject to abuse; however, the synthesis
of simple phenylethylamine derivatives would
not appear to offer the clandestine chemist any
advantage over the synthesis of methamphetamine.
The reasons for this statement are that pharmacological
studies have not identified other phenylethylamine
structures with stimulant activity appreciably
greater than methamphetamine and that either P2P
or the [beta]-hydroxyphenylisopropylamines are the
preferred precursors. However, in any case, the U. S.
CsA amendment should apply for all compounds
containing the phenylethylamine substructure.
The stimulant drugs phenmetrazine (preludin;
compound 23) and methylphenidate (ritalin; compound
22) are controlled under Schedule II of the
CFR. These compounds rank approximately half-way
between caffeine and amphetamine in potency (Meier
et al. 1954; Tripod et al. 1954a; Gruber et al. 1956).
The published synthesis of phenmetrazine, which
would seem to be most amenable to the clandestine
laboratory, is given in the work by Otto (Otto 1956).
The reaction involves the acid-catalyzed cyclization
of N-hydroxyethylnorephedrine (N-hydroxyethylphenylpropanolamine).
However, this reaction places
severe limits on the production of CsA's because
suitable precursors are limited. For instance, phenmetrazine
CsA could be prepared from compounds
such as N-ethyl-2,2-hydroxyphenyl-1-methylethylamine,
1,1-hydroxyphenyl-2-aminobutane, etc, but
limited commercial availability would generally
require synthesis of these compounds. Additionally,
the product CsA would clearly be perceived, even by
the untrained, as being structurally similar to phenmetrazine
and thereby would be a controlled substance
under the CsA amendment. Further, the
corresponding phenylethylamine which could be
made from these precursors, although also under the
purview of the CsA amendment, would most probably
have greater adrenergic activity than the phenmetrazine
derivative. Hence, clandestine production
of phenmetrazine CsA's would most likely be an
Pipradrol (compound 38, Figure 12) is a controlled
substance under CFR Schedule IV and can be
considered to be an analog derivative of methylphenidate.
Methylphenidate can be synthesized by the
method of Hartmann and Panizzon (1950). The
product exists as two diastereoisomeric enantiomer
pairs, one of which is the active stimulant, threo-dl-methylphenidate
(Weisz and Dudas 1960), while
the other is inactive as a stimulant. Threo-methylphenidate
accounts for only 20% of the final
reaction product (Rometsch 1958;1960). The synthesis
of pipradrol may be more amenable to the clandestine
laboratory as it is a relatively simple synthesis
and isolation of the final product is straightforward.
An appropriate C-2 substituted, N-protected piperidine
is a suitable precursor for what is essentially a
two step synthesis (Tilford et al. 1948; Werner and
Tilford 1953). Numerous derivatives of methylphenidate
and pipradrol have been synthesized with the
result that structure activity relationships have been
well defined (Scholz and Panizzon 1954; Tilford and
Van Campen 1954; Heer et al. 1955; Fabing 1955;
McCarty et al. 1957; Sheppard et al. 1960; Belleau
1960; Winthrop and Humber 1961; Portoghese and
Malspeis 1961; Wilimowski 1962; Lachman and Malspeis 1962).
There is little incentive, beyond the not
inconsiderable pressure of an already existing and
ready market, for producing clandestine CsA's of
methylphenidate. However, there are a number of
pipradrol derivatives described in the last cited references
which are suitable for clandestine production.
A best bet for a future CsA is the most potent
adrenomimetic compound in this series, 2-diphenylmethylpiperidine
(compound 39, Figure 12) (Tripod
et al. 1954b), which is estimated to be as potent as
methamphetamine (Sury and Hoffmann 1954). In
a very similar article to this paper, "Drugs of Abuse in
the Future," Shulgin (1975) suggested that levophacetoperane
(compound 40, Figure 12) could well be a
future clandestine CsA. However, this compound
shares the same limitations for clandestine synthesis
as does methylphenidate, in that only one diastereoisomer
is active (Jacob and Joseph 1960) and it is less
potent than methylphenidate (Dobkin 1960).
Although the phenylisopropylamine substructure
is an integral part of most known stimulants, the
well known and much abused stimulant, cocaine,
does not share this structural feature. The cocaine
molecule instead compares more closely to the structure
of acetylcholine. The synthesis of cocaine has
recently been revisited by Casale and many of the
procedural techniques are explained in sufficient
detail so that any competent organic chemist can now
make the C-3 equatorial cocaines (Casale 1987);
however, it is still a tedious and demanding synthesis,
and in my opinion will only be encountered on rare
occasions in clandestine laboratories. The particular
pharmacological behavior of cocaine is unquestionably
due in major part to the stereochemistry of the
molecule as determined by the fused bicyclic tropane
ring system (Clarke et al. 1973). Given the present
difficulties associated with the synthesis of the tropanes
and the ready availability of the natural product,
it is unlikely that a synthetic CsA of this
compound will appear in the near future. However, it
is the case that certain modifications of natural
cocaine can result in products having substantially
greater potencies than cocaine. The compounds
2-carbomethoxy-3-phenylnortropane are both some 60
times more potent than cocaine (Clarke et al. 1973).
These compounds could well be of interest to some
clandestine chemists as taking one kilogram or
cocaine and converting it into a product some sixty
times more potent would obviously be quite cost
In "Drugs of Abuse in the Future," Shulgin
(1975) directed attention to another stimulant which
also does not contain the phenylethylamine substructure
and, in fact, is reminiscent of the depressant
glutethimide. The compound is known commercially
as bemegride, 4-ethyl-4-methylpiperidine-2,6-dione,
and was first synthesized by Thole and Thorpe in
1911 (Thole and Thorpe 1911). The principal medical
use is as an analeptic in barbiturate poisoning. As a
stimulant, bemegride is approximately equal to phendimetrazine
and pemoline in potency. Although glutethimide
and bemegride are structurally similar, their
pharmacokinetics are diametrically opposed. Hence,
bemegride cannot be described as a CsA. Bemegride,
by virtue of being a stimulant, has an obvious
potential for abuse, although under the conditions of
abuse, rather large quantities of the drug will be
required. Increasing the possibility of bemegride
abuse are the facts that the synthesis of the compound
is not difficult and, of course, does not use
either a controlled or watched substance as a precursor
(Benica and Wilson 1950).
Depressants include such diverse chemical entities
as methaqualone, 5,5-disubstituted barbituric
acids, glutethimide and methyprylon, benzodiazepines,
chlorhexadol, chloral hydrate, paraldehyde,
meprobamate, and ethyl alcohol to name a few.
Historically in the U. S., the abuse of depressants,
alcohol aside, has been in major part confined to the
barbiturates, methaqualone, and the benzodiazepines.
Barbiturate abuse peaked in the mid 1970's
and has since become near nonexistent, in part no
doubt, to the well deserved bad press that the barbiturates
garnered. The abuse of methaqualone peaked
around 1980 and has also declined steadily since that
time. However, much counterfeit "lude" is still being
sold, but instead of containing methaqualone, the
tablets now often contain diazepam. Diazepam has
become the most prevalent depressant drug of abuse
and its use is apparently continuing to rise. It is
somewhat peculiar that of the many benzodiazepines
known and readily available in the legal commercial
market, diazepam is by far the most extensively
abused. The factors controlling this apparent user
preference for diazepam is certainly related, in part,
to simple product recognition; however, it is my
perception that the dominant factor is the ease with
which the drug can be diverted from the legitimate
market. In 1985 the legitimate diazepam market
consisted of 5 billion tablets (Franzosa 1985) and
since that time generic diazepam tablet production
has increased along with even greater product availability
for diversion into the illicit market (Franzosa,
E. personal communication).
A typical benzodiazepine synthesis is not be
considered difficult and a methaqualone synthesis is
quite straightforward (Grimmel et al. 1946). Further,
there is a great abundance of literature from which
the clandestine chemist can draw in deciding upon a
CsA based upon either the benzodiazepines or methaqualone
itself. However, with the very notable exception
of methaqualone, the clandestine syntheses of
depressant drugs in the U. S. have been extremely rare
(Franzosa, E. personal communication). It is not
likely that a clandestinely synthesized benzodiazepine
CsA will be encountered as long as the huge, easily
diverted legitimate supplies are at hand.
The use of methaqualone (compound 41, Figure
13) is in decline, but it will be with us as an abused
substance for still some time. Given the very large
numbers associated with the clandestine synthesis of
methaqualone, it is perhaps surprising that only two
CsA's of methaqualone (compounds 42 and 43,
Figure 13) have been analyzed at this laboratory.
Again, past history would suggest a high probability
for the appearance of new CsA of methaqualone in
the future. A CsA of methaqualone will by necessity
have the 3-aryl-quinazoline structure, and as a result
will fall under the CsA amendment. One would shell
predict that the driving force behind any future
clandestine synthesis of a methaqualone CsA will
revolve around attempts to use precursor materials
which will not alert law enforcement to the existence
of the clandestine laboratory. A literature review for
CsA candidates will quickly surface several possibilities
(Boissier and Piccard 1960; Camillo and David
1960; Jackman et al. 1960; Petersen et al. 1963;
Boehringer Sohn 1968a,b; Sumitomo Chemical Company
1968; Hurmer and Vernin 1968; Joshi and Singh
1973; 1974). One of the most intriguing methaqualone
CsA's from the perspective of a clandestine
chemist would have to be the halo- and thio- derivatives
described by Joshi et al. (1975). Two of the
compounds from this work (compound 44 and 45,
Figure 13) possess depressant activity greater than
methaqualone and compound 44 would be particularly
well suited to clandestine synthesis.
Literature covering the analgesics is so voluminous
that a review of the published data on the
subject is far beyond the scope of this work. Most of
the potent analgesics are modeled after features
found within the structure of morphine and some
literature detailing these structural features has been
published by Paul Janssen (Janssen 1960; 1961;
1962a,b; 1968). Despite a significant passage of time,
the structure activity relationships established in these
works still comprise a very sizable portion of our
empirical knowledge on this subject.
Some 13 years ago, Shulgin (1975) provided a short
overview of many of the known major classes of
analgesics. The following constitutes a similar listing:
Numerous works have dealt with the syntheses
and pharmacological testing of derivatives of the
structures listed above. Synthetic procedures have
been improved and refinements aimed at the tailoring
of specific analgesics to fulfill certain medical needs
have been addressed. However, it has been since 1975
that no work has been found introducing a new class
of analgesics of either unusual potency or particularly
well suited to synthesis in clandestine laboratories.
There has been discovered one compound which
may be of minor interest in that it is an analgesic with
potency similar to morphine and can be described as
a ring condensation product of N,N',3-trimethyl-5-hydroxytryptamine
(compound 46, Figure 14)
(Brossi 1985). In any discussion of synthetic anlagesics
one must include the so called Bentley compounds.
These compounds are not, in the purest
sense, synthetic analgesics as they are C-ring etheno
Diels Alder adducts of thebaine (Bentley et al.
1967a). Etorphine (compound 47, Figure 14) is perhaps
the best known compound in the series and has
analgesic activity approximately 1000 times that of
morphine (Bentley et al. 1967b; Hutchins et al. 1981).
Although reaction conditions appear to be critical,
the synthesis of etorphine derivatives involves what is
essentially a two step reaction with methylvinylketone
and an appropriate organometallic reagent (Haddlesey
et al. 1972; Hoogsteen and Hirshfield 1983).
Hence, the only expected difficulty in the clandestine
synthesis of these compounds would lie in the initial
acquisition of the thebaine. Therefore, it is somewhat
surprising that either etorphine or derivatives thereof
have not become a contributor to illicit analgesic
supplies. On the other hand, if etorphine were to be
admixed with some less potent analgesic, such as
heroin, it is doubtful that it would ever be detected.
- morphinans and isomorphinans
- pethidines (meperidines), prodines, and ketobemidones
- 3,3-diphenylpropylamines (methadone, propoxyphene)
- pirinitramide derivatives
In his 1975 article, Shulgin pointed to meperidine,
prodine, and ketobemidone as possible models
for "Drugs of Abuse in the Future." There are some
who think that Shulgin's comments were somewhat
of a self fulfilling prophecy as it is felt that his article
is well worn within the circles of clandestine laboratory
operators (Sapienza, F. personal communication).
Supporting this premise, at least to some extent,
is the fact that the appearance of the first known
fentanyl, China While, did not occur until 1979
(Henderson, G. 1.. personal communication). However,
it is also the case that desmethylprodine (MPPP;
compound 48, Figure 15) was first encountered in a
DEA laboratory sample submission in July of 1973
(Kram, T. personal communication), a full two years
before Shulgin published his article.
The probability that CsA's of prodine will constitute
any appreciable quantity of the clandestine
analgesic market in the future is relatively remote.
The well publicized neuro-toxicity of the prodine
dehydration product, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
(MPTP) (Langston et at. 1983; Markey
et al. 1985; Fries et al. 1986; Parkes 1986),
coupled with a limited scope of derivatives having
appreciable analgesic activity (Berger et al. 1947;
Ziering and Lee 1947; Beckett et al. 1957; Loew and
Jester 1975) would seem to remove prodine from
consideration as a model for CsA's. The fact that the
3-allyl analog of MPTP is not thought to be neurotoxic
(Brossi 1985) and the corresponding prodine
analog has greater analgesic activity than does
betaprodine (Ziering et al. 1957) may be of some
interest to the clandestine laboratory operator. However,
allylprodine (compound 49, Figure 15) is already
controlled under Schedule 1. A prodine derivative
which may be found in a future clandestine laboratory
is [alpha]-promedol, (Fries and Portoghese
1976). Analgesic activity for the unresolved stereoisomers
of promedol is approximately ten times that of
morphine, but there is some increased difficulty
associated with the synthesis and neurotoxicity for
it's MPTP analog is a real possibility. It is also the
case that [alpha]-promedol is listed in CFR Schedule
I under the name of trimeperidine.
In any event, the syntheses of prodine CsA's are
fraught with considerable risk from the inadvertent
production of either MPTP or an as yet unexplored
congener also having neurotoxic properties. It is
worth noting that at one time MPTP was tested for
use as an insecticide and that there are reports of
workers handling MPTP who have suffered full
blown Parkinsonian symptoms (Shafer, J. personal
Meperidine (pethidine, demerol; compound 50,
Figure 16) is approximately 50% as potent an analgesic
as is morphine and has a safety margin of only
4.8 as compared to 71 for morphine (Janssen 1985)
Hence, one would assume that the continued abuse
of meperidine is most probably related to the ease
with which it can be diverted from commercial channels
rather than it's applicability to drug abuse per se.
It has been noted that there are some 4000 compounds
which may be related chemically to meperidine
(Burger 1970). It should be pointed out that of
these 4000 compounds, many are not classified as
analgesics, and they must also include the closely
allied prodine and ketobemidone derivatives. The most
potent analgesics of the meperidine class of compounds,
as is the case with the prodine class of compounds,
all appear to already be controlled under
Schedule I and the less potent but clinically useful
derivatives controlled under Schedule II. The most
interesting compound from the view point of clandestine
synthesis would have to be phenoperidine (compound 51,
Figure 16) as analgesic activity is
approximately 30 times that of morphine and the safety
margin is increased, relative to meperidine, quite substantially
(Janssen 1985). Fentanyl (compound 52, Figure 17)
is an analgesic of high potency, approximately
300 times that of morphine, which was developed by
Janssen in 1962 (Janssen 1962b) and is
The first CsA of fentanyl came to the attention of law
enforcement in late 1979 but was not identified until
1981 (Allen et al. 1981). In the next three years a
procession of new fentanyl CsA's appeared in the illicit
drug market. The abuse of fentanyl CsA's peaked in
1985 and has since decreased dramatically (Henderson
1987), a phenomena which was the result of DEA
successfully terminating the operation of the responsible
laboratories. However, the ripple effect is still being
felt as international and national meetings have been
held to discuss the problems presented by CsA's. Also,
legislation, such as the U. S. CsA amendment, has been
passed in order to allow law enforcement to deal more
efficiently with the analog problem.
It is the author's opinion that fentanyl CsA's will
be back as the future analgesic drugs of abuse. The
thoughts behind this statement are that the published
synthesis schemes for the fentanyl compounds allow
for the use of wide variety of precursors as discovered
by the confiscated notes from an anonymous clandestine
laboratory that synthesized a drug, based on
information presented in two separate volumes of the
Journal of Organic Chemistry (Anon. 1957; Janssen
1962a; Riley et al. 1973; Van Bever et at. 1974; Van
Daele et al. 1976). Also, several fentanyl derivatives
have such high potencies that the quantities required
to be synthesized are trivial. For instance, carfentanil
(compound 53, Figure 17) is approximately 4000
times as potent as heroin and has an extremely
favorable therapeutic index (Janssen 1985). Hence, an
easy week's work for two chemists could provide 10
kilograms of carfentanil which would be equivalent to
40 metric tons of pure heroin.
In the course of this article, several points have
been made concerning those forces which will control
the appearance of future synthetic drugs of abuse.
The most important of these factors is user acceptance
of the marketed drug. Needless to say, the
typical clandestine drug dealer and/or chemist is not
overly concerned with the health of the user. However,
they are concerned with having a ready market
for their product. A reputation for selling "bad
stuff" would not be conducive to good business. A
recent example of this can be found in MPPP.
The second most important market controlling
factor is law enforcement control of the industry. A
recent example would be the effects produced when
P2P was placed under legal controls. The response so
far has been two fold; first there has been a concerted
move to either more fundamental precursors or to
synthetic routes utilizing [beta]-hydroxyphenylethylamines,
and second, there has been an apparent
increase in the abuse of 4-methylaminorex. Hence,
the methamphetamine market is in a state of flux as
a direct result of law enforcement activity and either
a CsA will be found which will provide both the user
and the clandestine drug chemist with the same advantages
as methamphetamine or a new precursor synthesis scheme
will be found which will offer nearly the same
advantages as P2P. It is axiomatic that for drugs of
moderate potency and high consumer demand, such as
methamphetamine, a synthesis scheme must be relatively
straightforward as it must be amenable to the
limited expertise available in the clandestine laboratories
in order to meet consumer demand.
In this work, only an occasional attempt was
made to address the difficulties associated with the
practical synthesis of the various derivatives discussed.
Some of the compounds discussed do not
have conveniently configured precursors that are
commercially available. Hence, synthesis of some of
these compounds require using the precursors earth,
fire, and water. Additionally, as the number and
complexity of substitution on any given chemical
structure increases, there is a corresponding increase
in the number of byproducts and a decrease in the
ultimate yield of target compound. In total then,
some of the compounds mentioned in this work are
not practical, especially considering the clandestine
laboratory, given the present state of synthetic knowledge.
However, as time moves on, more efficient and
direct methods of synthesis will be found and made
available to the informed reader through the scientific
literature. This point is easily exemplified even by the
work of our own forensic scientists (Sy and By 1984;
Casale 1987). The clandestine chemist of the future
will be more sophisticated than those of the present
and compounds not yet conceived of will be within
Consumer preferences and law enforcement
activities are the two dominate forces affecting
today's illicit drug markets. While staying within the
confines of consumer demand, the clandestine chemist
of the future will synthesize those drugs having the
highest possible potency in an effort to limit his
exposure to law enforcement activities and to expand
his illicit business as well.
Acknowledgement: The author wishes to
express his appreciation for the invaluable assistance
of Dr. Robert Klein, Ann Wimmers, and Charles
Harper in the preparation of this article.
ANALGESIC: 1) causing analgesia or freedom from pain.
2) a pain relieving remedy.
ANALOG: Compound with similar electronic structure
but different atoms.
CONTROLLED SUBSTANCES: are those drug substances which
are listed as of January 1, 1988 under schedules I through V of
the United States Title 21 Code of Federal Regulations (CFR)
section 1300 to end.
DERIVATIVE: An organic compound containing a
structural radical similar to that from which it is
derived, for example, benzene derivatives containing the benzene ring.
HOMOLOG: Member of a series of compounds whose structure
differs regularly by some radical, for example, methylene, from
that of its adjacent neighbors in the series.
SCHEDULE I: Schedule I is a listing of those
substances which are controlled under U. S.
federal laws, are deemed to have a high potential
for abuse, and for which there is no accepted
SCHEDULE II: Schedule II is a listing of those
substances which are controlled under U. S.
federal laws, are deemed to have a high potential
for abuse, and for which there is a accepted
Abood, L. C. and Biel, J. H. (1968). The psychotomimetic
glycolate esters. In: Drugs Affecting the Central
Nervous System. (Burger, A., ad.), l he Medicinal
Res. Series, Vol. 2, Dekker, NY, pp. 127.
Abood, L. I., Ostfeld, A. and Biel, J. AS. (1959).
Structure-activity relationships of 3-piperidyl
benzilates with psychotogenic properties, Arch.
Int. Pharmacodyn. 120:186.
Allen, A. C., Cooper, D. A. and Kram, T. (1981).
China white: [alpha]-methylfentanyl, Microgram,
Alles, C. A. (1959). Neuropharmacology transactions
of the Fourth Conference. (Abramson, to. A., ad.)
Madison Printing Co., Madison, NJ, pp. 181.
Angrist, B. M., Schweitzer, J., Friedhoff, A.J., Hershon,
S., Hekimian, L. J. and Floyd, A. (1969).
The clinical symptomatology of amphetamine
psychosis and its relationship to amphetamine
levels in urine, Int. Pharmacopsych. 2:125-139.
Anon. (1957) Synthesis of l-Phenylethyl-3-methyl-4-
(propananilido)- piperidine [3-methylfentanyl]
noted to be a modification of J. (Org. Chem.
12:901, 1947 and ibid. 22:152.
Avdovich, H. W., Beckstead, H. D., Dawson, B. A.,
Ethler, J-C., Latham, D., LeBelle, M., Laurlault,
G., Lodge, B. A. and Wilson, W L. (1987).
Identification of 4-ethoxy-2,5-dimethoxyam-
phetamine HCI (MEM), Microgram 20(3):37-47.
Barfknecht, C E. Nichols, D. E. Rusterhole, D. B.,
Long, J. B., Engelbrecht, J. A., Beaton, M. and
Dyer, D. C. (1973;. Potential psychotomimetics:
2-Amino-1,2,3,4-tetrahydronaphthalene, J. Med.
Beckett, A. H., Casy A. E. Kirk, a. and Walker, J.
(1957). Alpha- and beta-prodine type com-
pounds: configurational studies, J. Pharm.
Belleau, B. (l960). The synthesis of (+ -), (+0 and
(-) [alpha]- (3-thiamorpholinyl)-benzhydrol, a
new selective stimulant of the central nervous
system, J. Med. Pharm. Chem. 2:553-562.
Benica, W. S. and Wilson, C. O. (1950). Glutarimides
I. 3-Alkyl-3-methylglutarimides, J. Am. Pharm.
Bentley, K. W:, Hardy, D. C., Crocker, H. P., Had-
dlesey D. I. and Mayor, P. A. (1967a). Novel
analgesics and molecular rearrangements in the
morphine-thebaine group. VI. Base-catalyzed
rearrangements in the 6-14-endo-etheno-tetrahy-
drothebaine series, J. Am. Chem. Soc. 89:3312.
Bentley, K., Hardy, D. G. And Meek, B. (1967b).
Novel analgesics and molecular rearrangements
in the morphine-thebaine group. II. Alcohols
derived from 6,14-endo-etheno- and 6,14-endo-
ethanotetra-hydrothebaine, J. Am. Chem. Soc.
Berger, L., Ziering, A. and Lee, J. (1947). Piperidine
derivatives. IV. 4-alkyl-, 4-cycloalkyl-, and 4-
heterocycl-piperidines, J. Org. Chem. 12:901-
Biel, J.H., Nuhfer, P A., Hoya, K., Leiser, H. A.
and Abood, L. C. (1962). Cholinergic blockage
as an approach to the development of new
psychotropic agents, Ann. NY Acad. Sci. 96:
Boehringer Sohn, C. H. (1960). French patent, #
1,446,523 (Chem. Abstr. 66, 76030t, 1968) and
French patent, # 1,446,078 (Chem. Abstr. 66,
Boissier, J. R. and Piccard, t: E (1960). Therapie
Borella, L. E., Langis, A. and Charest, M. P. (1970).
Chemistry and pharmacology of new phenyl-
isopropylamine anorexiants, Chim. Ther. 5:247-
Braun, U. Shulgin, A. T. and Braun, G. (1980a).
Centrally active N-substituted analogs of 3,4-
edioxyamphetamine), J. Pharm. Sci. 69(2):192-
Braun, U., Shulgin, A. T. and Braun, G. (1980b).
Study of the central nervous activity and anagesia
of the N-substituted analogs of the amphet-
amine derivative, 3,4-methylenedioxyphenyli-
sopropyl-amine, Arzneim.-Forsch. 30:825-830.
Brossi, A. (1985). Further explorations of unnatural
alkaloids, J. Nat. Prod. 48(6):878-893.
Brown, C. E (1972). Hallucinogenic Drugs. (Kugel-
mass, I.N., ed.), Charles C. Thomas, Spring-
Burger, A. and Nara, S. (1965. In vitro inhibition
studies with homogeneous monoamine oxidases,
J. Med. Chem. 8:859.
Burger, A. (1970). In: Medicinal Chemistry. Wiley-
lnterscience, NY, pp. 1338.
Camillo, B. and David, A. (1960). The anticonvul-
sant properties of 2-methyl-3-p-bromophenyl-
3H-4-quinazolone hydrochloride and some
related compounds, J. Pharm. Pharmacol.
Casale, J. E (1987). A practical total synthesis of
cocaine's enantiomers, Forensic Sci. Int. 33:275-
Chen, C. (1958). Pharmacology of 1-(1-phenylcyclo-
hexyl)-piperidineHCl, Fed. Proc. 17:358
Clarke, R. L., Daum, S. J., Gambino, A. J., Aceto,
M. D., Pearl, J., Levitt, M., Cumiskey, W: R.
and Bogado, E. E (/973). Compounds affecting
the central nervous system. 4. 3[beta]-phenyltro-
pane-2- carboxylic esters and analogs, J. Med.
Connell, P H. (1958). Maudsley Monographs Num-
ber Five, Oxford University Press, London.
Cutting, W. C. (1969). Cutting's Handbook of Phar-
macology. Meredith, NY, pp. 512.
Daldrup, 7:, Heller, C., Mathiesen, U. Honus, S.,
Bresges, A. and Haarhoff, K. (1986).
Etryptamine, a new designer drug with fatal
effects, Z. Rechtsmed. 97(1):61-68.
deHaen, P. (1964). dehaen Nonproprietary Name
Index with Therapeutic Guide, Vol. 4, Paul
Dobkin, A. B. (1960). Drugs which stimulate affec-
tive behaviour. 2. Comparison of the analeptic
effect of d'amphetamine, bemegride with amin-
phenazole, methylphenidylacate, iproniazid
(micoren) and RP8228, Anaesthesia 15:146-153.
Fabing, H. D. (1955). New blocking agent against the
development of LSD-25 psychosis, Science
Franzosa, E. (1985). Solid dosage forms: 1975-1983,
J. Forensic Sci. 30(4):1194-1205.
Fries, D. S. and Portoghese, P. S. (1976). Stereochem-
ical studies on medicinal agents. 20. Absolute
configuration and analgetic potency of [alpa]-
promedol enantiomers. The role of the C-4 chiral
center in conferring stereoselectivity in axial- and
equatorial- phenyl prodine congeners, J. Med.
Fries, D. S. de Vries, J., Hazelhoff, B. and Horn,
A.S. (1986). Synthesis and toxicity toward
nigrostriatal dopamine neurons of 1- methyl-
analogues, J. Med. Chem. 29:424-427.
Gabriel, S. (1889). Ueber amidomercaptan, Chem.
Gabretcht. W. L. (1959). Synthesis of amides of
lysergic acid, J. Org. Chem. 24:368.
Garriott, J. C. (1975). Propylhexadrine-a new dan-
gerous drug?, Clin. Tox. 8(6):665-666.
Gill, E. W., Patron, W. D. M. and Pertwee, R. E.
(1970). Preliminary experiments on the chemis-
try and pharmacology of cannabis, Nature
Gessner, P. K., McIsaac, W. M. and Page, I. H.
(1961). Pharmacological actions of some meth-
oxyindolealkylamines, Nature, 190:179-180.
Gessner, P. K. and Page, I. H. (1962). Behavior
effects of 5-Methoxy- N, N-dimethyltryptamine,
other tryptamines and LSD, Amer. J. Physiol.
Godefroi, E. F., Maddox, V. H., Woods, H. and
Parcell, R. F. (1963). Process for Producing a
Depressant-like Effect on the Central Nervous
System. U. S, Patent # 3,097,136.
Goodman, L. S. and Gilman, A. (1970). The Phar-
macological Basis of Therapeutics. 4th Edition,
The MacMillian Co., London, pp. 646.
Govier, W. M., Howes, B. G. and Gibbons, A. J.
(1953). The oxidative determination of serotonin
and other 3-(beta-aminoethyl)-indoles by mona-
mine oxidase and the effect of these compounds
on the deaminatin of thramine, Science.
Grimmel, H.W., Guenther, A. and Morgan, J.F.
(1946). A new synthesis of 4-quinazolones, J.
Am. Chem. Soc. 68:542-543.
Gruber, K., Illig, H. and Pflanz, M. (1956). Deut.
Med. Wochschr. 81:1130.
Grunewald, G.L., Ruth, J.A., Kroboth, T.R.,
Kamdar, B. V., Patil, P.N. and Salman, K. N.
(1976). Conformationally defined adrenergic
agents I: Potentiation of levarterenol in rat vas
deferens by endo- and exo-2-aminobenzobicyclo
[2.2.2]octenes, conformationally defined ana-
logs of amphetamine, J. Pharm. Sci. 65(6):920-
Haddlesey, D.I., Lewis, J.W., Mayor, P.A. and
Young, G.R. (1972). Novel analgesics and
molecular rearrangements in the morphine- the-
baine group. Part XXIV. 15,16-didehydro-6,14-
endo-etheno- 6,7,8,14-tetrahydro-thebaines and
-oripavines, J. Chem. Soc. Perkin I pp. 872-874.
Hampton, W. H. (1961). Bull. NY Acad. Med.
Harris, L. S., Clarke, R. L. and Dembinski, J.R
(1963). a-Benzyltetrahydrofurfurylamines a new
series of psychomoter stimulants. III. The phar-
macology of D-threo a-benzyl-N-ethyltetrady-
drofurfurylamine (zylofuramine), Arch. Intern.
Harris, S. C. and Worly, R. C. (1957). Analgesic
properties of xylopropamine, Proc. Soc. Exp.
Biol. Med. 95:212-215.
Hartmann, M. and Panizzon, L. (1950). U.S. Patent
2,507,631 to Ciba Pharmaceutical Products Inc.
Heer, J., Sury, E. and Hoffmann, K. (1955). Uber
alkylenimin- derivate. Piperidin-derivate mit
zentralerregender Wirkung II, Helv. Chim. Acta.
Heinzelman, R. V., Anthony, W. C., Lyttle, D. A.
and Szmuszkovicz J. (1960). The synthesis of
[alpha]-methyltryptophans and [alpha]- alkyl-
tryptamines, J. Org. Chem. 25:1548-1558.
Heimann, V. H. and Vetter, K (1965) Klinische Unter-
suchungen mit einem neuen Psychostimulans (F-
1983), Schweiz. Med. Woch. 95:305-309.
Henderson, G. (1986). Designer Drugs: The New
Synthetic Drugs of Abuse. In: Proceedings of
Controlled Substance Analog Leadership Con-
ference. (Church, A. and Sapienza, F., eds.)
U. S. Department of Justice, Drug Enforcement
Administration, Office of Diversion Control.
Henderson, G. L. (1987). Designer Drugs: The Cali-
fornia Experience. presented at the Conference
on the Technical Aspects of Drug Controll, co-
sponsored by the World Health Organization
and the Drug Enforcement Administration,
Hochstein, F. A. and Paradies, A. M. (1957). Alka-
loids of Banisteria caapr and Prestonia amazoni-
cum, J. Am. Chem. Soc. 79:7535.
Hodgkins, J. E., Brown, S. D. and Massingill, J. L.
(1967). Two new alkaloids in cacti, Tetrahedron
Hollister, L. E. and Friedhoff, A. J. (1966). Effects of
3,4-dimethozyphenylethylamine in man, Nature
Hollister, L. E. and Gillespie, H. K. (1970). A new
stimulant, prolintane hydrochloride, compared
with dextroamphelamine in fatigued volunteers,
J. Clin. Pharm. 10:103-109.
Holmstedt, B., Daly, J. W., Del Pozo, E. C., Horn-
ing, E. C., Isbel, H. and Szara, S. (1967).
Discussion on the psychoactive action of various
tryptamine derivatives. In: Ethnopharmacologic
Search for Psychoactive l)rugs. (Efron, D. H.,
Holmsledt, B. and Kline, N. S., eds.) Public
Health Service Publication No. 1645.
Hoogsteen, K. and Hirshfield, J. (1983). Thebaine
and aetylenic dienophiles, J. Org. Chem.
Hoover and Hass (1947a). Synthesis of paredrine and
related compounds, J. Org. Chem. 12:501-505.
Hoover and Hass (1947b). Synthesis of 3-amino-
1-phenyl-1-propanoland its methylated deriva-
tives, J. Org. Chem. 12:506-509.
Horita, A. and Weber, L. J. (1961). Dephosphoryla-
tion of psilocybin to psilocin by alkaline phos-
phatase, Proc. Soc. Exp. Biol. Med. 106:32.
Howell, C. E. Quinor1es, N. Q. and Hardy, R. A.
(1962). 2-Amino-2- oxazolin-4-ones. 1. Synthe-
sis, J. Org. Chem. 27:1679-1685.
Huisgen and Lux (1960). Zum Mechanismus der
Phenylhydrazinsynthese nach E. Fischer, Chem.
Hurmer, R. and Vernin, (1968) British patent, #
1,093,977, Chem. Abstr. 68, 39648w.
Hutchins, C. US, Cooper, C. K., Purro, S. and
Rapoport, H. (1981). 6-Demethoxythebaine and
its conversion to analgesics of the 6,14- ethenom-
orphinan type, J. Med. Chem. 24(7):773-777.
Inaba, D. and Brewer, L. (1987). U4EUH, Micro-
Ippen, H. (1968). Index Pharmacorum-Synonyma,
Struktur und Wirkung der organisch-chemis-
chen Arzueistoffe. Georg Thieme Verlag, Stutt-
Jackman, C. B., Petrov, V. and Stephensen, O.
(1960). Some 2,3- disubstituted 3H-4-quinazo-
lones and 3H-4-thioquinazolones, J. Pharm.
Jacob, R. M. and Joseph, N. M. (1960). U. S. Patent,
# 2,928,835 to Rhone-Poulene.
Jacobs, UR A. and Craig, L. C. (1934). The ergot
alkaloids 11. The degradation of ergotinine with
alkali, J. Biol. Chem. 24:547-551.
Janssen, P A. J. (1960). In: Synthetic Analgesics,
Part I. Diphenylpropylamines. Pergamon Press,
London. pp. 1-183.
Janssen, P A. J. (1961). Pirintramide (R 3365), a
potent analgesic with unusual chemical struc-
lure, Research Papers, J. Pharm. Pharmaco.
Janssen, R A. (1962a). Chemical features associated
with morphine like activity, Anaesthesist 11:1-7.
Janssen, P A. (1962b). Review of the chemical fea-
tures associated with strong morphine Like activ-
ity, Brit. J. Anaesthesia 34:260-268.
Janssen, P A. J. and van der Lycken, C. A. M.
(1968). The chemical anatomy of potenl mor-
phine-like analgesics. In: Drugs Affecting the
Central Nervous System. (Burger, A, ed.) Dek-
ker, NY, pp. 25-60.
Janssen, P. A. J. (1985). The development of new
synthetic narcotics. In: Opiods in Anesthesia.
(Estafanous, F.G., ed.) Butterworth Publishers,
Boston, pp. 37-44.
Jordan, P. (1986). Hallucinogenic amphetamine
investigations. In: Proceedings Of Controlled
Substance Analog Leadership Conferellces
(Sapienza, E L. and A.C. Church, A. C., eds.)
U. S. Dept. of Justice, I)rug Fnlolcellle
Joshi, K. C. and Singh, V. K. (1973). Fluorinated
quinazolanes. Part I Synthesis and pharmalogi-
cal activity of some fluorinated 2-alkyl-3-aryl-
4(3H)-quanazolones and the corresponding
thioquanazolones, Indian J. Chem. 11:430-432.
Joshi, K. C. and Singh, V. K. (1974). Fluorinated
quinazolones: effect of some fluorinated 2-alkyl-
3-aryl-4(3H)-quinazolones and thioquanazolo-
nes on pyruvic acid oxidation, Indian .1. Exp.
Joshi, K. C., Singh, V. K., Mehta, D. S., Sharma, K.
C. and Gupta, L. (1975). Fluorinated quinazo-
lones III: Synthesis and CNS depressant activity
of fluorinated quinazolone derivatives, J.
Pharm. Sci. 64:1428-1430.
Kalir, A. and Pelah, Z. (1967). 1-Phenylcycloalky-
lamine derivatives. I, Israel J. Chem. 5:223-229.
Kalir, A., Edery, H., Pelah, Z., Balderman, D. and
Porath, G. (1969). 1-Phenylcycloalkylamine
derivatives. II. Synthesis and pharmacological
activity, J. Med. Chem. 12:473-477.
Kisakurek, M. V. and Hesse, M. (1980). Chemotax-
onomic studies of the apocynaceae, loganiaceae,
and rubiaceae, with reference to indole alka-
loids. In: The Annual Proceedings of the Phy-
tochemical Society of Europe Number 17,
(Phillipson, J.D. and Zenk, M. H., eds.) Aca-
demic Press, NY, pp. 11.
Klein, D. F. and Davis, J. M. (1969). Diagnosis and
Drug Treatment of Psychiatric Disorders,
Williams and Wilkins Co., Baltimore, MD.
Knoll, J., Vizi, E. S. and Ecseri, Z. (1966). Psycho-
mimetic methylamphetamine derivatives, Arch.
Int. Pharmacodyn. 159:442-451.
Kornfeld, E. C., Fornefeld, E. J., Kline, G. B.,
Mann, M. G., Jones, R. C. and Woodward, R.
B. (1954). The total synthesis of lysergic acid and
ergonovine, J. Am. Chem. Soc. 76:5256.
Lachman, L. and Malspeis, L. (1962). U. S. Patent, #
3,060,089 to Ciba Pharmaceutical Products Inc.
Langston, J. W, Bailard, P., Tetrud, J. W. and Irwin,
I. (1983). Chronic Parkinsonism in humans due
to a product of meperidine- analog synthesis,
Langston, J. W. and Rosner, D. J. (1986). The hazards
and consequences of the designer drug phenom-
enon: An initial approach to the problem. In:
Proceedings of Controlled Substance Analog
Leadership Conference, (Church, A. C. and
Lathrap, D. W. (1976). Ancient Ecuador Culture,
Clay and Creativity, 3000-300 B.C., Chicago,
IL: Field Museum of Natural History.
Liddell, D. W. and Weil-Malherbe, H. (1953). The
effects of methedrine and of lysergic acid dieth-
ylamide on mental processes and on the blood
adrenaline level, J. Neurol. Neurosurg. Psychiat.
Loew, G. H. and Jester, J. R. (1975). Quantum
chemical studies of meperidine and prodine, J.
Med. Chem. 18(11):1051-1056.
Maddox, V. H., Godefroi, E. F. and Parcell, R. F.
(1965). The synthesis of phellcyclidine and other
1-arylcyclohexylamines, J. Med. Chem. 8:230-
Mannich, and Jacobsohn (1910). Uber oxyphenyl-
alkylamine und dioxyphenyl-alkylamine, Chem.
Ber. 43: 189.
Markey, S. P., Castagnoli, N., Kopin, I. and Trevor,
A. (198S. In: MPTP-a Neurotoxin Producing
a Parkinsonian Syndrome. Academic Press, NY.
Marsh, D. F. and Herring, D. A. (1950). The phar-
macological activity of the ring methyl substi-
tuted phenisopropylamines, J. Pharmacol. Exp.
McCarty, F. J., Tilford, C. H. and Van Campen, M.
G. (1957). Central stimulants. [alpha],[alpha]-
disubstituted 2-piperidinemethanols and 1,1-dis-
ubstituted heptahydrooxazolo[3,4-a]pyridines, J.
Am. Chem. Soc. 79:472-480.
McGlothlin, W. H. (1971). Amphetamines, Barbitu-
rates, and Hallucinogens: An Analysis of Use,
Distribution and Control. SCID-TR-2, United
States Department of Justice, Drug Enforcement
Administration, pp. 98.
Meier, R., Gross, F. and Tripod, J. (1954). Klim.
Naranjo C., Shulgin, A. T. and Sargent, T. (1967).
Evaluation or 3,4 methylenedioxyamphetamine
(MDA) as an adjunct to psychotherapy, Med.
Pharmacol. Exp. 17:359-364.
Naranjo, C. (1967). In: Ethnopharmacological
Search for Psychoactive Drugs. (Holmstedt, B.,
ed.) Department of Health, Education, and Wel-
fare, Washington, DC, pp. 385-391.
Nied, J. and Smith, R. M. (1982). Identification of
fencamfamine, Microgram 15(10):168-172.
Otto, W. G. (1956). Angew. Chem. 68:181.
Parke, Davis & Co. (1960). Brit. Pat. #836,083.
Parke, Davis & Co. (1963). U. S. Pat. #3,097,136.
Patil, P. N. and Yamauchi, D. (1970). Influence of the
optical isomers of some centrally acting drugs on
norepinephine responses, Eur. J. Pharmacol.
Peterson, R. C. and Stillman, R. C. (1978). Phencyc-
lidine (PCP) Abuse: An Appraisal. NIDA
Research Monograph #21, National Institute on
Drug Abuse, Rockville, MD.
Parkes, D. (1986). In: MPTP and the Aetiology of
Parkinson's Disease. J. Neural Trans. Sup. 20.
Petersen, S., Tietze, E., Hoffmeister, E. and Wirth,
W. (1963). British patent, # 932,680.
Portoghese, P. S. and Malspeis, L. (1961). Relative
hydrolytic rates of certain alkyl (b) dl-[alpha]
(2-Piperidyl)-phenylacetates, J. Pharm. Sci.
Riley, T. N., Hale, D. B. and Wilson, M. C. (1973).
4-Anilidopiperi- dine analgesics I. Synthesis and
analgesic activity of certain ring-methylated 1-
substituted 4-propananilidopiperidines, J.
Pharm. Sci. 62(6):983-986.
Robie, T. R. (1961). A new and safer monoamine
oxidase inhibitor, J. Neuropsychiat. 2:(Suppl. 1)
Robinson, B. (1983). The Fischer Indole Synthesis,
Robinson, T. (1968). The Biochemistry of Alkaloids,
Verlag, NY, pp. 77.
Rometsch, R. (1958). U. S. Patent, # 2,838,519 to
Ciba Pharmaceutical Products Inc.
Rometsch, R. (1960). U. S. Patent, # 2,957,880 1,
Ciba Pharmaceutical Products Inc.
Rosengarten, E (1969). The Book of Spices, Living
ston Publishing Company, Philadelphia, PA, pp.
Rothlin, E. (1957a). Lysergic acid diethylamide and
related substances, Ann NY Acad. Sci. 66:668.
Rothlin, E. (1957b). Pharmacology of LSD, .1
Pharm. Pharmacol. 9:569.
Schaeffer, J. C., Cho, A. K., Glenn, T. N. and Glenn,
S. T. (1975). Inhibition of synaptosomal accu-
mulation of l-norepinephrine I: N.- arylalkyl and
N-aryloxyalkyl dl-amphetamines and related
compounds, J. Pharm. Sci. 64(9):1462-1469.
Schneider, J. A. and Siggs, E. B. (1957). Neurophar-
macological studies on ibogaine, an indole alka-
loid with central-stimulant properties, Ann. NY
Acad. Sci. 66:765-776.
Scholz, K. and Panizzon, L. (1954). Uber die darstel-
lung von pyridyl- und piperidyl-aryl-acetonitrilen
und einigen Umwandlungs-produkten, Helv.
Chim. Acta. 37:1605.
Schultes, R. E. (1938). The Appeal of Peyote (Lopho-
phora williamsii) as a medicine, Am. Anthropol.
Schultes, R. E. (1940). The aboriginal therapeutic
uses of Lophophora williamsii. Cactus Succulent
Sheppard. H., Tsien, W. H., Rodegker, W. and
Plummer, A. J. (1960). Distribution and elimi-
nation of methylphenidate-C14, Toxicol. Appl.
Shoemaker, D. W, Bidder, T. G., Boettger, H. G.,
Cummins, J. T. and Evans, M. (1979). Com-
bined gas chromatography and mass spectrome-
try of aromatic B-carbolines, J. Chromatogr.
Shulgin, A. T. (1964). Psychotomimetic amphet-
amines: methoxy 3,4-dialkoxyamphetamines,
Shulgin, A. T. (1969). Psychotomimetic agents
related to the catecholamines, J. Psychedelic
Shulgin, A. T., Sargent, T. and Naranjo, C. (1969).
Structure-activity relationships of one-ring psy-
chotomimetics, Nature 221:537-541.
Shulgin, A. T. (1970). Psychotomimetic Drugs.
(Efron, D.H., ed.) Raven, NY.
Shulgin, A. T. (1975). Drugs of abuse in the future,
Clin. Tox. 8(4):405-456.
Smissman, C. E and Pazdernik, T. L. (1973). A
conformational study of phenethylamine recep-
tor sites. 1. Syntheses of semirigid analogs of
[beta]-methylamphetamine, J. Med. Chem. 16:
Smith, S. (1927). 1-Methylephedrine, an alkolyd from
ephedra species, J. Chem. Soc. 2056-2059.
Smythies, J. R., Johnston, V. S. and Bradley, R. J.
(1969). Behavioural models of psychosis, Brit. J.
Snyder, S. H. and Richelson, E. (1970). Steric models
of drugs predicting psychedelic activity. In: Psy-
chotomimetic Drugs. (Efron, D., ed.) Raven,
NY, pp. 43.
Spalla, C. (1980). Production of ergot alkaloids by
fermentation. In: The Annual Proceedings of
the Phytochemical Society of Europe Number
17, (Phillipson, J.D. and Zenk, M.H., eds.)
Academic Press, NY, pp. 273-283.
Spath, E. (1919). Uber die Anhalonium-alkaloids I.
Anhalin und Mezcalin, Mh Chem. 40:129.
Speeter, M. E. and Anthony, W. C. (1954). The action
of oxalyl chloride on indoles: A new approach to
tryptamines, J. Am. Chem. Soc. 76:62()8-621().
Sumitomo Chemical Company (1968). British
patent, # 1,054,718 Chem. Abstr. 66, 76031u.
Sury, E. and Hoffmann, K. (1954). Uber Alkylen-
imin-derivate. Piperidin-derivate mit zentralerre-
gender Wirkung I, Helv. Chim. Acta. 37:2133-
Sy, W-W. and By, A. W (1984). A more efficient
synthesis of 2,3,5-trimethoxyamphetamine using
nitryl iodide, NO21, Microgram 17(12):179-191.
Szara, S. and Hearst, E. (1962). The 6-hydroxylation
of tryptamine derivatives. A way of producing
psychoactive metabolites, Ann. NY Acad. Sci.
Szara, R., Rockland, L. H., Rosenthal, D. and
Handlon, J. H. (1966). Psychological effects and
metabolism of N,N-diethyltryptamine in man,
Arch. Gen . Psychiat . 15: 321.
Szara, S. (1970). DMT (N,N-dimethyltryptamine)
and homologues: Clinical and pharmacological
considerations. In: Psychotomimetic Drugs.
(Efron, D., ed.) Raven, NY, pp. 275.
Thole, E B. and Thorpe, J. E (1911). The formation
and reactions of amino-compounds. Part XV.
The production amino-derivatives of peperidine
leading to the formation of B-disubstituted glu-
taric acids, J. Chem. Soc. 99:422-448.
Tilford, C. H. and Van Campen, M. C. (19S4).
Diuretics. [alpha],- [alpha]-disubstituted 2-pipe-
ridine-ethanols and 1,3-disubstituted octa-
hydropyrid[1,2-c]oxazines, J. Am. Chem. Soc.
Tilford, C. H., Shelton, R. S. and Van Campen, M.
G. (1948). Histamine antagonists. Basically sub-
stituted pyridine derivatives, J. Am. Chem. Soc.
Traube, W. and Ascher, R. (1913). Uber das isohy-
dantoin 2-imino- 4-keto-tetrahydro-oxazol und
seine Homologen, Chem. Ber. 46:2077.
Treptow, K. R., Affleck, D. C., Roehl, C. A. and
Soelling, W. M. (1963). Nylidrin hydrochloride
in senile arteriosclerosis, Arch. Neurol. 9:142-
Tripod, J., Bein, H. J. and Meier, R. (1954a). Char-
acterization of central effects of serpasil (reser-
pin, a new alkaloid of Rauwolfia serpentina B.)
and of their antagonistic reactions, Arch. Intern.
Tripod, J., Sury E. and Hoffmann, K. (1954b).
Zentralerregende Wirkung eines neven Pipe-
ridinderivates, Experientia 10:261-262.
Turner, W. J. (1963). Experiences with primary proc-
ess thinking, Psychiatr. Q. 37:476-488.
Turner, W. J., Merlis, S. and Carl, A. (1955). Con-
cerning theories of indoles in schizophrenigene-
sis, Am. J. Psychiat. 112:466-467.
Usdin, E. and Efron, D. H. (1972). Psychotropic
Drugs and Related Compounds, 2nd edition,
Department of Health, Education, and Welfare,
Van Bever, W. F. Niemegeers, C. J. E. and Janssen,
P. A. J. (1974). Synthetic analgesics. Synthesis
and pharmacology of the dia- stereoisomers of
phenylpropanamide and N-[3-methyl-1-(1-
panamide, J. Med. Chem. 17:1047-1051.
Van Daele, P. G. H., De Bruyn, M. F. L., Boey, J. M.,
Sanczuk, S., Agten, J. T. M. and Janssen, P A. J.
(1976). Synethic analgesics: N-(1-[2-arylethyl]-
4-substituted 4-piperidinyl) N-arylalkanamides.
Aezneim.-Forsch, (Drug Res.) 26(8):1521-1529.
Weisz, I. and Dudas, A. (1960). Uber Stereoisomere
shefte fur Chemie 91:840-849.
Werner, H. W. and Tilford, C. H. (1953). U. S.
Patent, # 2,624,739 to the Wm. S. Merrell Co.
Whaley, W. M. and Govindachari, T. R. (1951).
Organic Reactions. Vol 6. Wiley, NY, pp. 151
Wilimowski, M. (1962). Arch. Immunol. Terappii
Winthrop, S. O. and Humber, L. G. (1961). Central
stimulants. Cyclized diphenylisopropylamines
J. Org. Chem. 26:2834-2836.
Wooley, D. W. (1962). The Biochemical Bases of
Psychoses or the Serotonin Hypothesis about
Mental Disease, John Wiley & Sons, NY.
Zbinden, G., Randall, L. O. and Moe, R. A. (1960).
Dis. of Nerv. Sys. 21:89.
Ziering, A. and Lee, J. (1947). Piperidine derivatives
V. 1,3- Dialkyl-4-aryl-4-acyoxypiperidines, J.
Org. Chem. 12:911-914.
Ziering, A., Motchane, A. and Lee, J. (1957). Pipe-
ridine derivatives. IV. 1,3-Disubstituted-4-aryl-
4-acyloxy piperidines, J. Org. Chem. 22:1521