Replacing the 1,3-benzodioxole group in MDMA (ecstasy) with a 1,3-benzoxathiole yields two analogues, SDA and SDMA, that interact with monoamine transporters similarly to MDMA but with key differences. SDA and SDMA inhibit dopamine and norepinephrine transporters more potently than MDMA and act as partial releasers at serotonin and dopamine transporters. Metabolism studies show SDA and SDMA are cleared faster, while MDMA and MDA degrade only weakly. In mice, SDMA does not produce rewarding effects, unlike MDMA, and SDA only shows a preference for the drug-paired compartment at the lowest dose. SDMA shares similar locomotor and hyperthermic profiles with MDMA, whereas SDA induces increased hyperlocomotion and more sustained hyperthermia. SDMA may be a safer candidate for further study.
Selectivity for the 5-HT2A receptor over the closely related 5-HT2C receptor can be achieved by targeting residue L1232.53 in transmembrane 2 of the extended binding pocket through increasing steric aliphatic bulk on the α-methylene group of the N-benzyl chemical scaffold. This selectivity was confirmed across 5-HT2C RNA editing isoforms, TM2 reciprocal mutants, and mouse orthologs, producing the most highly selective 5-HT2A agonists to date. Using structure–activity relationships, molecular docking, and mouse head-twitch response assays, the work demonstrates that such agonists can be rationally designed to improve target engagement, advancing the study of the neurobiological mechanisms of psychedelic effects.