Trifluoromethyl ring‐substituted methcathinone analogs: activity at monoamine uptake transporters

Abstract

The psychostimulant effects of methcathinone result from inhibition of uptake and promotion of release of biogenic amines via the uptake transporters for serotonin (SERT), norepinephrine (NET), and dopamine (DAT). To explore the influence of chemical structure on activity at these transporters, we synthesized trifluoromethyl (CF3) positional analogs of methcathinone with a CF3 substituent at the 2-, 3-, or 4-position of the phenyl ring. We tested these compounds for their abilities to inhibit [3H]5-HT (SERT) or [3H]NE (NET) uptake, and as [3H]5-HT (SERT) or [3H]MPP+ (NET, DAT) releasing agents. At SERT, the 3-CF3 and 4-CF3 analogs were at least 10-fold more potent than methcathinone itself as uptake inhibitors and releasers, but the 2-CF3 analog was both a poor uptake inhibitor and a weak releaser. At NET, on the other hand, all the CF3-methcathinone analogs were less potent than methcathinone as uptake inhibitors and releasers, with IC50 and EC50 values in the low μM range. The CF3 derivatives were also less potent (30- to 400-fold) than methcathinone as [3H]MPP+ releasers at DAT. These results support the hypothesis that substitutions at the 3- or 4-positions of phenylalkylamines enhance activity at SERT and also suggest a structural approach (2-substitution) for creating compounds that are selective for catecholamine transporters versus serotonin transporters. Support: DA017675 (NVC) and IRP, NIDA, NIH.