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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.
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.
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.