Synthesis and Pharmacological Evaluation of Ring-Methylated Derivatives of 3,4-(Methylenedioxy)amphetamine (MDA)
Matthew Parker, Danuta Marona‐lewicka, Deborah M. Kurrasch, Alexander T. Shulgin, David E. Nichols
Journal of Medicinal Chemistry February 24, 1998 DOI: 10.1021/jm9705925 via OpenAlex
Summary
Adding a methyl group to the 2 or 5 position of the ring of MDA produces compounds that are more potent and more selective than MDA itself at releasing serotonin in rat brain tissue. The 2-methyl and 5-methyl derivatives were tested in rats trained to distinguish serotonin-releasing drugs from saline, confirming their activity in living animals. These compounds are among the most potent serotonin-releasing agents known and may serve as leads for developing antidepressants that work by releasing serotonin rather than blocking its reuptake.
Study at a glance
| Characteristics | In vivo and in vitro pharmacological study Peer reviewed |
|---|---|
| Population | Rat brain synaptosomal preparations and live rats |
| Topics | Serotonin |
| Keywords | Methylenedioxy Pharmacology Hallucinogen Amphetamine |
| Citations | 25 |
| Key finding | The 2-methyl and 5-methyl derivatives of MDA are more potent and selective than MDA in releasing serotonin and are among the most potent serotonin-releasing compounds known. |
Abstract
The three isomeric ring-methylated derivatives of the well-known hallucinogen and entactogen MDA (1a) were synthesized and evaluated for pharmacological activity as monoamine-releasing agents and as serotonin agonists. The 2-methyl derivative 2a and the 5-methyl derivative 2b were found to be more potent and more selective than the parent compound in inhibiting [3H]-serotonin accumulation in rat brain synaptosomal preparations. Their activity in vivo was confirmed in rats trained to discriminate serotonin-releasing agents and hallucinogens from saline. The results indicate that compounds 2a,b are among the most potent 5-HT-releasing compounds known and show promise as lead compounds in the search for antidepressant drugs that release serotonin rather than inhibit its uptake.