Introduction of a methyl group in alpha- or beta-position of 1-heteroarylethyl-4-phenyl-piperazines affects their dopaminergic/serotonergic properties

Abstract

1-(2-Heteroarylalkyl)-4-phenylpiperazines containing methyl group in either the alpha- or the beta-position of the side alkyl chain were synthesized as racemic mixtures. They were evaluated for in vitro binding affinity at the D-1 and D-2 dopamine and 5-HT1A serotonin receptors using synaptosomal membranes of the bovine caudate nucleus and hippocampus, respectively, as a source of the corresponding receptors. Tritiated SCH 23390 (D-1 receptor-selective), spiperone (D-2 receptor-selective), and 8-OH-DPAT (5-HT1A receptor-selective) were employed as the radioligands. None of the new compounds expressed significant affinity for the D-1 receptor. Introduction of the methyl group into the beta-position of the parent molecules increased the affinity for the D-2 receptor (10b-13b), and decreased the affinity for the 5-HT1A receptor with the exception of imidazole (11b) which was a rather efficient displacer of 8-OH-DPAT. Most potent of the newly synthesized compounds in [H-3]spiperone assay were compounds (+/-)6-[1-methyl-2-(4-phenylpiperazin-n-1-yl)-ethyl]-1, 4-dihydroquinoxaline-2,3-dione (10b), K-d = 6.0 nM and (+/-)5-[1-methyl-2-(4-phenylpiperazin-1-yl)-ethyl]-1,3-dihydrobenzoirnidazol-2-thione (13b), K-d = 5.3 nM. However, compounds containing methyl group in alpha-position (10a-13a) of the parent molecules expressed a decreased affinity for the D-2 receptor, while the affinity for the 5-HT1A receptor remained in the same range of concentrations as that of closely related achiral parent compounds (14-17) run in the same binding assays as references.