title: Introduction of a methyl group in alpha- or beta-position of 1-heteroarylethyl-4-phenylpiperazines 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 D1 and D2 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 (D1 receptor-selective), spiperone (D2 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 D1 receptor. Introduction of the methyl group into the beta-position of the parent molecules increased the affinity for the D2 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 [3H]spiperone assay were compounds (+/-)6-[1-methyl-2- (4-phenylpiperazin-1-yl)-ethyl]-1,4-dihydroquinoxaline-2,3-dione (10b), Kd = 6.0 nM and (+/-)5-[1-methyl-2-(4-phenylpiperazin-1-yl)-ethyl]-1,3-dihydrobenzoimidazol- 2-thione (13b), Kd = 5.3 nM. However, compounds containing methyl group in alpha-position (10a-13a) of the parent molecules expressed a decreased affinity for the D2 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.
authors.affiliation: Faculty of Chemistry, University of Belgrade, 11000 Belgrade, Studentski trg 12-16, Yugoslavia.
authors.forename: G
authors.initials: G
authors.lastname: Roglic
authors.forename: D
authors.initials: D
authors.lastname: Andric
authors.forename: S
authors.initials: S
authors.lastname: Kostic-Rajacic
authors.forename: S
authors.initials: S
authors.lastname: Dukic
authors.forename: V
authors.initials: V
authors.lastname: Soskic
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D015259:Dopamine Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D011869:Radioligand Assay; D011954:Receptors, Dopamine / Q000378:metabolism; D011985:Receptors, Serotonin / Q000378:metabolism; D018490:Serotonin Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D015259:Dopamine Agents; D010879:Piperazines; D011954:Receptors, Dopamine; D011985:Receptors, Serotonin; D018490:Serotonin Agents