Development of 3-Phenyltropane Analogues with High Affinity for the Dopamine and Serotonin Transporters and Low Affinity for the Norepinephrine Transporter

摘要

Previous studies showed that the mixed monoamine transporter inhibitor (6, RTI-112) reduced cocaine self-administration at a high level of serotonin transporter (5-HTT) occupancy with no detectable dopamine transporter (DAT) occupancy. In this study, a series of 3 beta-(substituted phenyl)tropane-2 beta-carboxylic acid methyl esters (7a-g), 3 beta-(4-methoxyphenyl)tropane-2 beta-carboxylic acid esters (8a-j), and 3 beta-(4-methoxyphenyl)-2 beta-[3-(4'-methylphenyl)isoxazol-5-yl]tropane (9) were synthesized and evaluated for their monoamine transporter binding affinities to identify potent and selective compounds for both the DAT and 5-HTT relative to the norepinephrine transporter (NET). A number of compounds showed high binding affinities for both the DAT and 5-HTT and low affinity for the NET. 3 beta-(4-Methoxyphenyl)tropane-2 beta-carboxylic acid 2-(3-iodo-4-aminophenyl)ethyl ester (8i) with an IC50 value of 2.5 nM for the DAT and K-i values of 3.5 and 2040 nM for the 5-HTT and NET, respectively, is the most potent and selective compound for the DAT and 5-HTT relative to the NET in this study.