Allosteric modulators of the dopamine transporter (DAT) have previously been identified. In this study, analogs of these ligands were synthesized, evaluated for activity, and discussed. The compounds were divided into three groups of [3H]dopamine ([3H]DA) uptake inhibitors: 1) full efficacy agents with a one-site fit, 2) full efficacy agents with a two-site fit, and 3) partial efficacy agents with a one-site fit. The partial efficacy agents partially inhibited DA, serotonin, and norepinephrine uptake, but were much less potent at inhibiting [3H]WIN35428 ([3H]2β-carbomethoxy-3β-(4-fluorophenyl)tropane) binding to DAT. These agents did not alter DAT-mediated release of [3H]MPP+ ([3H]1-methyl-4-phenylpyridinium) in the absence or presence of 100 nM d-amphetamine, demonstrating the existence of potent DAT ligands that partially block [3H]DA uptake without affecting DAT binding or d-amphetamine–induced [3H]MPP+ release.
See article at J Pharmacol Exp Ther 2015, 353:529–538.
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