Structure-affinity relationship studies on D-2/5-HT1A receptor ligands. 4-(2-Heteroarylethyl)-1-arylpiperazines.
With an aim of creating new, mixed D-2/5-HT1A ligands, sixteen different compounds were synthesized. For this purpose 1-arylpiperazines attached through N-4 nitrogen to the dopaminergic pharmacophores of 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 their structural diversity (phenyl, substituted phenyl, heteroaryl and naphthyl). All new compounds were checked for in vitro binding affinity at the dopamine (D-1 and D-2) and serotonin (5-HT1A) receptors. Synaptosomal membranes prepared from fresh bovine caudate nuclei and hippocampus were used as a source of dopamine and serotonin receptors, respectively, [3H]SCH 23390 (D-1 selective), [3H]spiperone (D-2 selective) and 8-OH-[3H]DPAT (5-HT1A selective) were employed as the radioligands. All compounds were inactive competitors of [3H]SCH 23390, 1c and 2b being inactive in the two other binding assays, as well. Derivatives of 1-(2-pyridyl)piperazine 1b and 2a and of 1-phenylpiperazine 1a expressed moderate to low affinity for both D-2 and 5-HT1A receptors, while 1-(2-pyridyl)-piperazines 3b and 4b and 4-(1-phenylethyl)-1-(1-naphthyl)-piperazine 10 were moderate [3H]spiperone, but potent 8-OH-[3H]DPAT competitors. Among them, derivatives of 1-(1-naphthyl)-piperazine 1e, 2d and 3e and of 1-(2,3-dimethylphenyl)-piperazine 1d, 2c and 3d were the strongest competitors at both D-2 and 5-HT1A receptors.
Dukić
S
S
Institute for Biological Research, Faculty of Chemistry, University of Belgrade, Yugoslavia.
Vujović
M
M
Soskić
V
V
Joksimović
J
J
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000378:metabolism; D000818:Animals; D001552:Benzazepines / Q000378:metabolism; D002417:Cattle; D002421:Caudate Nucleus / Q000187:drug effects; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D018492:Dopamine Antagonists / Q000378:metabolism; D065127:Dopamine D2 Receptor Antagonists; D006624:Hippocampus / Q000187:drug effects; D066298:In Vitro Techniques; D008024:Ligands; D010879:Piperazines / Q000138:chemical synthesis* / Q000494:pharmacology; D017448:Receptors, Dopamine D2 / Q000187:drug effects; D011985:Receptors, Serotonin / Q000187:drug effects*; D018490:Serotonin Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000378:metabolism; D013134:Spiperone / Q000378:metabolism; D013329:Structure-Activity Relationship; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism
D001552:Benzazepines; D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; D008024:Ligands; D010879:Piperazines; D017448:Receptors, Dopamine D2; D011985:Receptors, Serotonin; D018490:Serotonin Agents; D017366:Serotonin Receptor Agonists; D013134:Spiperone; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin