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  • AADD Moderators: swilow | Vagabond696

Chemical Evolution: From MDMA to MMAI

phase_dancer

phase_dancer

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"The Chemical Evolution from Ecstasy to Selective Serontonin Reuptake Transporter Substrates"
David Nichols, Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmaceutical Sciences, Purdue University, West Lafayette, IN 47907.
Serotonin is an important neurotransmitter in the brain. Dr. Nichols has been focused on the role of serotonin on behavior, and sought an understanding to the mechanism of action of the recreational drug 3,4-methylenedioxymethamphetamine ("ecstasy"). In doing so, his lab developed MMAI, which is a selective serotonin releasing agent (SSRA). Instead of inhibiting the reuptake of serotonin from the neuronal synapse (like the SSRI drug, fluoxetine), it encourages release of serotonin from pre-synaptic stores. The end result is the same: an increase of serotonin in the synaptic cleft. Compared to SSRIs such as fluoxetine (Prozac), Nichols' data suggests that SSRAs may have therapeutic value. SSRAs have a faster onset and more robust antidepressive effects than SSRIs, according to Nichols. In addition, Nichols claims that SSRAs are not neurotoxic, and unlike SSRIs, do not depend on tonic activity of serotonin neurons in order to exert their effects.
pic_proxie.jpg

It's not likely anyone will see this chem on the streets any time soon. The only known synthesis is complicated. Even the starting material Methyl-3-Methoxy-benzaldehyde is not available commercially.
David Nichols is a remarkable chemist. Here's a little on his research.
From: Purdue University
The general thrust of the work in our laboratory could be characterized as the development of molecular probes to understand the role of brain monoamine neurotransmitters in normal behavior. Although molecular biology has made great strides in providing information about structural and functional aspects of the brain, those studies must be complemented through the use of specifically designed molecules that are directed toward particular biological targets. In an academic sense, such molecules are useful in gaining fundamental information about neuronal function. When one of them has high efficacy and low toxicity, however, it may become a drug candidate.
We have a particular focus on brain systems that utilize dopamine or serotonin as the neurotransmitter. In the former case, we are interested in molecular probes that have specificity for only one of the five general types of dopamine receptors (D1 - D5). Our efforts to date have led to several novel benzo[a]phenanthridines and naphthoisoquinolines that are full efficacy agonists at the dopamine D1 receptor subtype. One of these (named Dihydrexidine) showed remarkable efficacy in an animal model of late stage Parkinson's disease. A second-generation compound named dinapsoline has properties similar to dihydrexidine. Dinapsoline now has also shown dramatic efficacy in both rodent and primate models of Parkinson's disease. Recently we have developed yet a third series of related compounds based around a prototype named dinoxyline. By appropriate structural modifications, these different templates have led to molecules with specificity for the D2 or D3 dopamine receptor isoforms.
We also have a continuing interest in the serotonin 5-HT2A and 5-HT2C receptors as likely targets for hallucinogenic/psychedelic substances and atypical antipsychotic drugs, and the possible roles that these receptor systems may play in normal cognitive function. These projects are comprised of systematic structural modification, coupled with pharmacological assay, with a view toward identifying structural determinants of the ligand binding domain in these receptors. One theme of this work has been to identify how molecules from different chemical classes can all be accommodated within the same receptor binding site.
More recently we have been studying the second messenger systems that are coupled to the 5-HT2A receptor, and investigating their relative importance in the actions of hallucinogenic drugs. We have also developed a computer-based homology model of several G protein coupled receptors and are attempting to understand the functional elements within the receptor that are key to agonist activation.
Click to expand...
 
Hmmm, the drug itself may not be neurotoxic, but it would still bring about the unfavourable effect of depleting serotonin stores, right?
Any huge shift in a biological equilibrium is still going to cause many bad things to happen to the body, specially with such an important chemical as serotonin. So, it's not neurotoxic, it's still going cause undue pressure on the body. Don't raise your hopes yet.
 
Good read alright.
Seratonin levels can be replenished at least though through diet. I'd be more interested to see if the body builds up tolerance.
As far as non-neurotoxic analogues of MDMA go, well there is always MDAI or MDMI. The only problem is that it is as about as rare as a Jason Midro set that's worth listening to.
 
As Nichols’s work has involved examining mechanisms of MDMA induced neurotoxicity, and specifically the role of dopamine, this compound is likely the result of further examination of compounds which mimic MDMA without producing dopamine increases (thought to be related to MDMA toxicity). Nichols’s development and synthesis of MBDB and MDAI provided evidence to support early proposed DA /neurotoxicity models.
This compound really caught my attention. The substance has no methylenedioxy bridge, which makes the geometry of the molecule somewhat different to MDMA, MBDB or MDAI etc. Shulgin had spoken of the idea that maybe MDMA isn’t an active drug but is merely a pro drug – a substance which by itself is inactive, but is converted by the body’s enzymes to an active drug. Making such a drug and getting it into the brain and then having it do its thing before it too is smashed by enzymes, was considered to be quite a task. Perhaps this is the type of substance Shulgin was talking about last year. (E conference Feb. 2001)
When looking at MDMA, it has been shown that the 2 oxygens in the methylenedioxy bridge (see above MDMA, the “arrow head” bit sticking off the benzene ring) differ greatly in their contribution towards the toxicity of the molecule. Replacement of one O with other groups - CH2, S etc. - resulted in change in activity but retained neurotoxicity. Replacement of the other (4th in above post) produced some compounds which retained activity but reduced neurotoxicity. These molecules would have been designed from SAR models of the time, and probably some pretty healthy speculation. It could also turn out that this latest - MMAI - was conceived early on, but proved initially too hard to synthesize.
This journal article is where much of the early development of these substances is collated. If anyone has this I would very much appreciate a view, as my Uni doesn’t subscribe to this publication
J. Med. Chem. 1993, 36, pp.3700-3706
As for depleting brain serotonin reserves, I hasten to speculate whether this is a perfect drug in this sense, although to be non-neurotoxic by definition implies it would not deplete serotonin. Whether this is dose or frequency dependant is another thing. I think MMAI should be considered a possible step towards such “ideal” drugs. Ideal being the qualities of an MDMA experience without the health, psychological and other problems; the once a month or once a year Prozac if you like.
We are possibly along way off from producing a drug like this, but as to other applications of this research in neuro-pharmacology, such as developing preventatives and treatments for Alzheimer’s and Parkinson’s, this is already happening.
Thanks to the chief bee and psychokitty for the info source.
 
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