Systematic Structure–Activity Studies on Selected 2‑, 3‑, and 4-Monosubstituted Synthetic Methcathinone Analogs as Monoamine Transporter Releasing Agents

Methcathinone analogs are appearing on the clandestine market at a rate nearly out-pacing the ability of investigators to examine them on an individual basis. To formulate structure–activity relationship (SAR) generalities, we examined the releasing ability of several simple methcathinone analogs at the three monoamine transporters (i.e., the dopamine, norepinephrine, and serotonin transporters, DAT, NET, and SERT, respectively) using in vitro assay methods. The analogs included methcathinone and 14 other compounds monosubstituted at the 2-, 3-, or 4-position. In general, (a) the 2-substituted analogs were less potent than either the 3- or 4-substituted analogs, (b) the 3- and 4-substituted analogs were relatively similar in potency, (c) methcathinone was the most selective as a DAT-releasing agent, and (d) the 3- and 4-CF₃ analogs were the least DAT-selective. For the 15 compounds, there was a significant correlation (r > 0.9) between DAT and NET potency, suggesting relatively similar structure–activity relationships (at least for the compounds examined here). Several of the compounds have appeared on the clandestine market since our studies were initiated, and the present results provide new information on how they might act.