Introduction of a methyl group in α‐ or β‐position of 1‐heteroarylethyl‐4‐phenyl‐piperazines affects their dopaminergic/serotonergic properties

1‐(2‐Heteroarylalkyl)‐4‐phenylpiperazines containing methyl group in either the α‐ or the β‐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‐HT 1A 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‐HT 1A 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 β‐position of the parent molecules increased the affinity for the D 2 receptor ( 10b—13b ), and decreased the affinity for the 5‐HT 1A 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 [ 3 H]spiperone assay were compounds (±)6‐[1‐methyl‐2‐(4‐phenylpiperazin‐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‐dihydrobenzoimidazol‐2‐thione ( 13b ), K d = 5.3 nM. However, compounds containing methyl group in α‐position ( 10a—13a ) of the parent molecules expressed a decreased affinity for the D 2 receptor, while the affinity for the 5‐HT 1A 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.