We previously reported that methcathinone, the aryl ketone analog of methamphetamine, was an inhibitor of monoamine uptake into human platelets and cultured cells (Cozzi et al., Soc. Neurosci. Abs., 24, 341.8, 199
. Based upon our pharmacophore model for the amphetamine binding site in the plasma membrane serotonin (5-HT) uptake transporter, it was hypothesized that halogen substituents on the phenyl ring of methcathinone would have a favorable effect on binding affinity at the 5-HT transporter. To test this proposal, 3-bromomethcathinone and 4-bromomethcathinone were synthesized and evaluated for their abilities to inhibit [3H]5-HT uptake into human platelets in vitro. In support of our hypothesis, both of the bromine-substituted compounds were about 15-fold more potent than methcathinone as 5-HT uptake inhibitors: 3-bromomethcathinone inhibited [3H]5-HT uptake with an IC50 of 2.05 ± 0.17mM while 4-bromomethcathinone had an IC50 of 1.83 ± 0.5 mM These results lend support to our model of the substrate binding site in the 5-HT uptake transporter. The model predicts that there is a pocket within the substrate binding domain of the transporter that can accommodate substituents at the ring meta-or para-positions of arylalkylamine ligands. Occupation of this pocket by such substituents leads to increased stability of the ligand-protein complex.