Synthesis of several substituted phenylpiperazines behaving as mixed D-2/5HT(1A) ligands

Twenty-two different compounds have been synthesized with the aim of creating new, mixed D-2/5HT(1A) ligands. For this purpose 1-substituted phenylpiperazines attached by the N-4 nitrogen to dopaminergic pharmacophores of the 2-(5-benzimidazole)ethyl-, 2-(5-benztriazole)ethyl-, 2-[5-(benzimidazole-2-thione)]ethyl- and 2-[6-(1,4-dihydroquinoxaline-2, 3-dione)] ethyl-type were selected according to known structure-affinity requirements of 1-arylpiperazines. All the new compounds were evaluated for in-vitro binding affinity at the dopamine (D-1 and D-2) and 5-HT1A receptors. Synaptosomal membranes prepared from fresh bovine caudate nuclei and hippocampi were used as a source of dopamine and 5-hydroxytryptamine receptors, respectively. [H-3]SCH 23390 (D-1 selective), [H-3]spiperone (D-2 selective) and 8-OH-[H-3]DPAT (5-HT1A selective) were employed as the radio-ligands. None of the compounds expressed affinity for binding at D-1 dopamine receptors. Compounds 3b and 4b were inactive 8-OH-[H-3]DPAT competitors whereas 1b, 2b and 4b were inactive in the [H-3]spiperone-binding assay. The other compounds tested showed fair (1c, 1e, 1f, 2c, 2f, 3b, 3c and 4c) to high (1a, 1d, 2a, 1d, 3a, 3d-3f, 4a, and 4d) affinity in the [H-3]spiperone-binding assay, the most potent representative being 4-[2-(5-benzimidazole-2-thione)ethyl] -1-(2-methoxyphenyl)piperazine, 3a (K-i = 1.7 nM). In the 8-OH-[H-3]DPAT-displacement assay compounds 1b, 1d, 1f, 2b, 2f and 3f behaved as moderate competitors and la, Ic, le, 2a, 2c, 2d, 3a, 3c-3e, 4a, 4c, 4d and 4f as rather strong competitors; 4-[2-(5-benztriazole)ethyl]-1-(2-methoxyphenyl)piperazine, 2a had the highest binding affinity at the 5-HT1A receptors (K-i = 2.6 nM). Because many antipsychotic and anxiolytic agents behave as mixed dopaminergic and serotonergic ligands, the high affinity of several of these new ligands for binding at both D-2 and 5-HT1A receptors make them promising candidates deserving further pharmacological evaluation as antipsychotic or anxiolytic pharmaceuticals.