Society for Neuroscience Abstracts, 25, 678.17 (1999)
Abstract
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, 1998). 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.
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