Stereoselectivity of pleiotropic monoamine transporter 2-benzoylpiperidine inhibitors and their potential application as novel pharmacological tools.

2-Benzoylpiperidines (BPs; 1a) represent a novel class of dopamine transporter (DAT) reuptake inhibitors. Although displaying substantial selectivity for DAT versus serotonin transporters (SERT), they had not been examined at the remaining member of the monoamine transporter (MAT) family: the norepinephrine transporter (NET). Here, several racemic BPs were examined at NET, individual optical isomers were synthesized and examined at DAT and NET, modeling/docking studies were performed to predict the potencies of the compounds/isomers at MATs, and mutant DAT and NET transporters were constructed and examined to test binding hypotheses. BPs were less potent at NET than at DAT, 2-(3,4-dichlorobenzoyl)piperidine (DCBP; 1b) was predicted to bind with high affinity at DAT due to possible halogen bond formation between the 3-chloro substituent and SER149, R isomers were identified as eutomers at DAT and NET, and this is supported using transporters where SER149 in DAT (or its cognate amino acid in NET) was mutated to an alanine residue.