Dual DAT/σ1 receptor ligands based on 3-(4-(3-(bis(4-fluorophenyl) amino) propyl) piperazin-1-yl)-1-phenylpropan-1-ol

Ester analogs of (+/-) 3-(4-(3-(bis(4-fluorophenyl)amino)propyl)piperazin-1-yl)-1-phenylpropan-1-ol were synthesized and evaluated for binding at DAT, SERT, NET, and sigma 1 receptors, and compared to GBR 12909 and several known sigma 1 receptor ligands. Most of these compounds demonstrated high affinity (K(i) = 4.3-51 nM) and selectivity for the DAT among the monoamine transporters. S- and R-1-(4-(3(bis(4-fluorophenyl)amino)propyl)piperazin-1-yl)-3-phenylpropan-2-ol were also prepared wherein modest enantioselectivity was demonstrated at the DAT. However, no enantioselectivity at sigma 1 receptors was observed and most of the ester analogs of the more active S- enantiomer showed comparable binding affinities at both DAT and sigma 1 receptors with a maximal 16-fold DAT/sigma 1 selectivity. Published by Elsevier Ltd.