Mixed dopaminergic/serotonergic properties of several 2-substituted 4-[2-(5-benzimidazole)ethyl]-1-arylpiperazines

Abstract

A series of substituted 4-[2-(5-benzimidazole)ethyl]-arylpiperazines was synthesized by introducing different substituents into position 2 of benzimidazole ring of 4-[2-(N,N-di-n-propylamino)ethyl]-1,2-diaminobenzenes. They were evaluated for in vitro binding affinity at the D 1 and D 2 dopamine and 5-HT(1A) serotonin receptors using synaptosomal membranes of the bovine caudate nuclei and hippocampi, respectively. Tritiated SCH 23390 (D 1 receptor-selective), spiperone (D 2 receptor selective),and 8-OH-DPAT (5-HT(1A) receptor selective) were employed as the radioligands. Only compound 6 expressed a moderate binding affinity at the dopamine D 1 receptor, while the remaining ligands were inefficient or weak competitors of [ 3 H]SCH 23390. Compound 12 was an absolutely inactive competitor of all three radioligands. Also, compound 7 was an inefficient displacer of [ 3 H]-8-OH-DPAT. Compound 19 with a K(i) value of 3.5 nM was the most potent competitor of [ 3 H]spiperone and compound 13 (K(i) = 3.3 nM) was the most efficient in displacing [ 3 H]-8-OH-DPAT from the 5-HT(1A) serotonin receptor. Ligands 5, 6, 8-11, and 13-20 expressed mixed dopaminergic/serotonergic activity in nanomolar range of concentrations with varying affinity ratios which strongly depended on the properties of the substituents introduced into position 2 of benzimidazole ring of the parent compounds.