The benzylic ketone analogs of the psychoactive phenylisopropylamine methamphetamine (MA), MCAT, and of 3,4-methylenedioxymethamphetamine (MDMA), MDMCAT, were synthesized and compared to the nonketo compounds for their abilities to inhibit reuptake transporter-mediated [3H]serotonin accumulation into human platelets. MCAT inhibited [3H]serotonin uptake into platelets with an IC50 of 33.7 ± 9.0 mM while MA exhibited an IC50 of 11.7 ± 1.0 mM; this difference was not significant. The methylenedioxy-substituted compounds were about 6-fold more potent (p < 0.05) than the unsubstituted compounds in this assay; MDMCAT displayed an IC50 of 5.8 ± 0.7 mM and MDMA had an IC50 of 2.1 ± 0.3 mM. The difference in potency between MDMCAT and MDMA was significant at p < 0.01. These results indicate that beta-keto derivatization of psychoactive phenylalkylamines does not have a major impact on the drugs' ablility to inhibit serotonin uptake and that phenyl ring substitutions can enhance potency.
