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Ravina E, Casariego I, Masaguer CF, Fontenla JA, Montenegro GY, Rivas ME, Loza MI, Enguix MJ, Villazon M, Cadavid MI, Demontis GC: Conformationally constrained butyrophenones with affinity for dopamine (D (1), D (2), D (4)) and serotonin (5-HT (2A), 5-HT (2B), 5-HT (2C)) receptors: synthesis of aminomethylbenzo [b] furanones and their evaluation as antipsychotics. J Med Chem. 2000 Nov 30;43(24):4678-93.
A series of novel conformationally restricted butyrophenones (6-aminomethyl-4,5,6,7-tetrahydrobenzo [b] furan-4-ones bearing 4-(6-fluorobenzisoxazolyl) piperidine, 4-(p-fluorobenzoyl) piperidine, 4-(o-methoxyphenyl) piperazine, 4-(2-pyridyl) piperazine, 4-(2-pyrimidinyl) piperazine, or linear butyro (or valero) phenone fragments) were prepared and evaluated as antipsychotic agents by in vitro assays for affinity for dopamine receptors (D (1), D (2), D (4)) and serotonin receptors (5-HT (2A), 5-HT (2B), 5-HT (2C)), by neurochemical studies, and by in vivo assays for antipsychotic potential and the risk of inducing extrapyramidal side effects. Potency and selectivity depended mainly on the amine fragment connected to the cyclohexanone structure. Compounds 20b, with a benzoylpiperidine moiety, and 20c, with a benzisoxazolyl fragment, were selective for 5-HT (2A) receptors. The in vitro and in vivo pharmacological profiles of N-[(4-oxo-4,5,6, 7-tetrahydrobenzo [b] furan-6-yl) methyl]-4-(p-fluorobenzoyl) piperidine (20b, QF1003B) and N-[(4-oxo-4,5,6, 7-tetrahydrobenzo [b] furan-6-yl) methyl]-4-(6-fluorobenzisoxazol-3-yl) p iperidine (20c, QF1004B) suggest that they may be effective as antipsychotic (neuroleptic) drugs. |
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