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From: sknight@tartarus.uwa.edu.au (Sam Knight)
Newsgroups: alt.psychoactives
Subject: Re: LSD analogues (was re: ALD-52)
Date: 3 Oct 1994 12:33:28 GMT
Message-ID: <36otmo$jfn@styx.uwa.edu.au>

Christopher Hemming (CJHEMMIN@SCIENCE.watstar.uwaterloo.ca) wrote:
: While we're on the subject of LSD analogues, I understand that replacing
: the methyl group on nitrogen 6 with ethyl, allyl or propyl results in 
: compounds of similar, or even higher (by a factor of 2-3) potency.  Is
: this right?  I'm pretty sure I've actually looked up the paper, but of
: course it was just a glance at it.  So, is that right?

I have seen that too. The reference was posted along with a reference to
the JACS article on sythesis of lysergic acid methyl ester from L-tryptophan
and some article on the synthesis of LSD from LSA using POCl3.
I think the post is available for FTP.

: I find it interesting that the LSD molecule is so sensitive to substitution.
: There aren't many substitutions that will retain activity (just a couple
: of types, as compared with the psychedelic phenethylamine family where you
: can do just tons of stuff).  It must be fitting into that receptor pocket
: really nicely.  Especially the diethylamine group.  I understand just 
: about any other substitution pattern there pretty much abolishes activity.
: Hmm.  I wonder if you replaced some of the -H's on those two ethyl groups
: with -F's...  That would keep the size about the same, but would change the
: charge distribution.  Has it been tried?  -F for -H is supposed to be a
: fun substitution in bioactive molecules, often modifying activity since 
: it's the same size (roughly) as -H, but is a lot harder for enzymes to 
: take off.  Apparently monofluoroacetic acid is one of the most generally
: toxic substances known (i.e. bad for most life forms) because it gets into
: some important pathway (related to carbon oxidation,  Kreb's cycle?) and
: totally fucks it all to hell.

There are other LS amides that _are_ active at dosages less than 20x that of
LSD including ALD-52, d-LS morpholide (20% LSD activity), 1-N-methyl LSD
(40% activity), d-LS dimethylamide (10%), d-LS ethylamide (5%) and
d-(1-N-methyl-LS-pyrrolidide) (7%)
I think research into fluroLSDs has been a bit limited (I certainly
havent seen any in my wandering, and it being a fairly notorious
sheduled drug must put a bit of a damper on human trials..)
It is, however, a good idea..
Does anyone have information on the breakdown path of LSD, I think
it is metabolised by MAO. Certainly MAOIs increase LSD potency.

: Also, -Cl lies somewhere between -H and -CH3 in size (or so I'm told) so 
: making of the ethyl groups a 2-chloroethyl group wouldn't be quite as 
: bad size-wise as making it a propyl group (which apparently abolishes 
: activity).  Of course, 2-chloroethyl ethyl amine would polymerize/cyclize 
: nicely.  Maybe it wouldn't be too easy to work with, so a different 

sure looks that way..

: synthesis might be required rather than just using a different amine in
: the amidation step.  But I don't really know what I'm talking about, I'm
: just throwing out ideas.

you and me both :)


: ------------------------------------------------------------------------------
:                   FIRST CHURCH OF CHRIS ORGANIC CHEMIST
:                              Waterloo, Ont.
:   Better living through chemistry -- For every problem, a chemical solution.
: ------------------------------------------------------------------------------

Sam