From: [d--n] at [cam.ov.com] (Donald T. Davis)
Newsgroups: alt.drugs,alt.psychoactives,sci.med.psychobiology
Subject: Re: MDMA Neurophamacology
Date: 23 Jun 1994 22:46:04 -0400

this message comprises an exchange of several messages between me
and matt plunkett, which followed his responding to my comments about
mdma's neurotoxicity. it starts out with a lot of technical matter,
which matt clarified as the conversation progressed. i figured you
all might be interested, so i'm posting it.
							-don davis

~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~

Don wrote:
> it sounds like the psychological action may depend on the
> neurotoxicity, though they could just share a common cause.

matt responded:

TITLE:           Nonneurotoxic tetralin and indan analogues of
                   3,4-(methylenedioxy)amphetamine (MDA).
                 [Nonneurotoxic tetralin and indan analogues of 3 4
                   methylenedioxyamphetamine mda]
AUTHOR:          Nichols, D E (Dep. Med. Chem., Sch. Pharmacy Pharmacal Sci.,
                   Purdue Univ., West Lafayette, Indiana 47907.); Brewster, W
                   K; Johnson, M P; Oberlender, R; Riggs, R M
PUBLICATION:     Journal Of Medicinal Chemistry. 1990 33(2):702-710.
                 J Med Chem.
ABSTRACT:  Four cyclic analogues of the psychoactive phenethylamine derivative
   3,4-(methylenedioxy)amphetamine were studied. These congeners, 5,6- and
   4,5-(methylenedioxy)-2-aminoindan (3a and 4a, respectively), and 6,7- and
   5,6-(methylenedioxy)-2-aminotetralin (3b and 4b, respectively) were tested
   for stimulus generalization in the two-lever drug-discrimination paradigm.
   Two groups of rats were trained to discriminate either LSD tartrate (0.08
   mg/kg) from saline, or (.+-.)-MDMA.cntdot.HCl (1.75 mg/kg) from saline. In
   addition, a 2-aminoindan (5a) and 2-aminotetralin (5b) congener of the
   hallucinogenic amphetamine 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane
   (DOM) were also evaluated. None of the methylenedioxy compounds substituted
   in LSD-trained rats, while both 3a and 3b fully substituted in MDMA-trained
   rats. Compounds 4a and 4b did not substitute in MDMA-trained rats. Compounds
   5a and 5b did not substitute in MDMA-trained rats, although 5a substituted
   in LSD-trained rats, but with relatively low potency compared to its
   open-chain counterpart. In view of the now well-established serotonin
   neurotoxicity of 3,4-(methylenedioxy)amphetamine and its N-methyl homologue
   1, 3a and 3b were evaluated and compared to 1 for similar toxic effects
   following a single acute dose of 40 mg/kg sc. Sacrifice at 1 week showed
   that neither 3a nor 3b depressed rat cortical or hippocampal 5-HT or 5-HIAA
   levels nor were the number of binding sites (Bmax) depressed for
   [3H]paroxetine. By contrast, and in agreement with other reports, 1
   significantly depressed all three indices of neurotoxicity. These results
   indicate that 3a and 3b have acute behavioral pharmacology similar to 1 but
   that they lack similar serotonin neurotoxicity.

Oxidation at the 6-position on the aromatic ring creates the toxic
metabolite; blocking this position creates a non-neurotoxic, equally effective
analogue . . . 

matt (Matthew James Plunkett <[p--nk--t] at [uclink.berkeley.edu]>)

On Thu, 23 Jun 1994, Donald T. Davis wrote:

> thanks for your response, but while i think i got the punchline,
> i certainly didn't understand the prologue (though i'd like to).
> the main obstacle for me was the notion of lsd substituting for
> the other drugs (which i guessed are relatives of mdma). what's
> this notion of substitution, please?
> 						-don
> 
matt responded,

The idea is that you get a rat to tell the difference between lsd
and saline, and between mdma and saline.  If you take an mdma trained rat
and give it lsd, it doesn't know the difference between lsd and saline.
So it's a crude way to tell the differences between drug classes.

So these molecules they made, some of them, showed cross substitution
with mdma.  The logical next experiment would be to give them to a human
and have her record what happens. . .

Take care,
matt

don replied:

ok, now i understand the abstract (thanks for the explanation).
and, now that i understand, i stick to my guns after all: it may
be that mdma's permanent effects depend on the neurotoxicity, even
though the temporary effects do not.

						-don davis
						 boston, ma