Developing non-neurotoxic recreational drugs

[Heretic.Ape.]

Interesting little thing I stumbled upon at World Intellectual Property Organization dealing with making non-neurotoxic drugs via avoidance of simultaneous stress on dopamine and serotogenic systems.
h.a.

http://www.wipo.int/pctdb/en/wo.jsp?...5&DISPLAY=DOCS
WO 2007069925 20070621
Title
Non-neurotoxic recreational drugs and a method of treating recreational drug abuse.
5 Field of the Invention


This invention relates to recreational drugs and in particular to recreational drugs which are non-neurotoxic and/or to methods of treating recreational drug abusers.


I O Background of the Invention


Recreational drugs such as 3,4-methylenedioxy-N-methylamphetamine, commonly known as "MDMA" or "Ecstasy", are widely used around the world. The chemical formulation of MDMA is shown below:

MDMA is known to cause selective serotonergic neurotoxicity in both animal and human recreational users. This neurotoxicity was first reported in the 1980s but its mechanism was not elucidated until the early 1990s. It has now 0 been demonstrated that MDMA neurotoxicity results from the inappropriate reuptake of dopamine into serotonergic neurons followed by MAO-B catalysed oxidation of the dopamine leading to lipid peroxidation and subsequent destruction of cell structures. Neurotoxicity thus requires unnaturally prolonged and excessive release of both serotonin and dopamine at the same time. 5 Additional evidence suggests that the toxic hyperthermia seen in MDMA overdose may be linked to excessive release of noradrenalin.


The multiple effects of MDMA have now been elucidated through research. MDMA has three targets in the brain that are important to its action.
Firstly it binds to the 5HTT serotonin reuptake transporter and causes it to run in reverse, effectively pumping serotonin from the neuron body back out into the synapse. Secondly it binds to the VMAT-2 vesicular monoamine transporter. This stimulates vesicular release of serotonin, dopamine and noradrenalin, in a similar manner to other amphetamines.
Thirdly MDMA binds weakly to the 5HT2A receptor which causes the hallucinations of LSD, mescaline etc. MDMA has only mild effects at this target and does not characteristically induce hallucinations.


In order to separate the different effects of MDMA, compounds were developed that would bind selectively to each of the different targets. Animals were then trained to distinguish between the three separate cues, which were labelled "empathogenic", "stimulant" and "hallucinogenic".
Compounds selective for the hallucinogen cue (selective 5HT2A agonists) were already known, and include compounds such as LSD, DOM, psilocin and mescaline, with well established activity. Compounds selective for the stimulant cue are non-selective releasers of dopamine, serotonin and noradrenalin (via vesicular release triggered by VMAT-2 binding). These compounds are very dangerous and often induce toxic hyperthermia, convulsions, stroke etc. Some examples of these compounds have made their way onto the illicit market and include drugs such as paramethoxyamphetamine (PMA) and 4-methylthioamphetamine (4MT), both of which have been responsible for multiple deaths in humans.


Compounds were also developed that were selective for the "empathogenic" cue, acting specifically as 5HTT "inverse agonists" to selectively release serotonin with no effect on dopamine or noradrenalin release. These compounds were found to mimic many of the effects of MDMA in animal studies, yet produced no serotonergic neurotoxicity when administered by themselves.


Three compounds that fitted this profile were originally developed. Subsequently several more have been discovered. These compounds are not amphetamines.


The carbon skeleton has been modified in such a way that amphetamines could
not be produced from them in any useful quantity. These compounds have all been shown to mimic some MDMA effects yet produce no measurable serotonergic toxicity in animals even following chronic administration of high doses.


As abuse of MDMA is a current problem that is almost certainly causing some degree of brain damage to human users of this known neurotoxin, there have been attempts to develop a non-neurotoxic replacement for MDMA. One such attempt is the benzylpiperazine/trifluoromethylphenylpiperazine products currently available on the market, but while these products simulate MDMA effects in animals, they are not adequate substitutes for human MDMA users.
There are also problems associated with the piperazine products (especially when they are combined with alcohol) including abuse potential, unpleasant side effects and isolated incidents of blackouts and convulsions.


Due to the increasing amount of recreational drug users worldwide there is a need to develop less harmful recreational drugs which do not cause neurotoxicity and which would therefore reduce the amount of harm suffered by recreational drug users without necessarily changing their patterns of drug use.


Object of the Invention


It is an object of the invention to provide a recreational drug which is non- neurotoxic and/or a method of treating recreational drug abusers, or at least to provide the public with a useful choice.


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I'm not much of a pharmacology buff so I'd be interested in hearing more knowledgeable folks discuss this.

Reputation Comments on this post:

Very interesting.