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 σ1 receptors, and compared to GBR 12909 and several known σ1 receptor ligands. Most of these compounds demonstrated high affinity (Ki = 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 σ1 receptors was observed and most of the ester analogs of the more active S-enantiomer showed comparable binding affinities at both DAT and σ1 receptors with a maximal 16-fold DAT/σ1 selectivity.