Synthesis and dopaminergic properties of 3- and 4-substituted 1-{2-[5-(1H-benzimidazole-2-thione)]ethyl}piperidines and related compounds

With an aim of creating new, high affinity dopaminergic ligands, six different 3- and 4-substituted 1-{2-[5-(1H-benzimidazole-2-thione)]ethyl}piperidines and nine related heterocyclic congeners were synthesized and evaluated for in vitro binding affinity at D-1 and D-2 dopamine receptors. Synaptosomal membranes prepared from fresh bovine caudate nuclei were used as a source of the dopamine receptors. Only 4-[bis-(4-fluorophenyl)methylene]piperidines, compounds 9e, 10d, and lid, expressed moderate affinity for the D-1 receptors, while all other compounds were inactive competitors of [H-3]SCH 23390. Compounds 9c, 9d, 10c, 11a, and Ile were inactive in the D-2 receptor binding assay, as well. Derivatives of 4-phenylpiperidine (9-11b) and 3-phenylpiperidine (10a) expressed a moderate to low affinity for the D-2 receptors. However, racemic (+/-)-1-{2-[5-(1H-benzimidazole-2-thione)]ethyl}-3-phenylpiperidine 9a and its enantiomer (+)-9a behaved as selective, high affinity D-2 receptor ligands, the latter being some four times more active than the racemate.