Synthesis of Several Substituted Phenylpiperazines Behaving as Mixed D2/5HT1A Ligands

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Abstract
Twenty‐two different compounds have been synthesized with the aim of creating new, mixed D2/5HT1A 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 (D1 and D2) 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. [3H]SCH 23390 (D1 selective), [3H]spiperone (D2 selective) and 8‐OH‐[3H]DPAT (5‐HT1A selective) were employed as the radio‐ligands. None of the compounds expressed affinity for binding at D1 dopamine receptors. Compounds 3b and 4b were inactive 8‐OH‐[3H]DPAT competitors whereas 1b, 2b and 4b were inactive in the [3H]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 [3H]spiperone‐binding assay, the most potent representative being 4‐[2‐(5‐benzimidazole‐2‐thione)ethyl]‐1‐(2‐methoxyphenyl)piperazine, 3a (Ki = 1.7 nm). In the 8‐OH‐[3H]DPAT‐displacement assay compounds 1b, 1d, 1f, 2b, 2f and 3f behaved as moderate competitors and 1a, 1c, 1e, 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 (Ki = 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 D2 and 5‐HT1A receptors make them promising candidates deserving further pharmacological evaluation as antipsychotic or anxiolytic pharmaceuticals.