Conformationally constrained butyrophenones with affinity for dopamine (D-1, D-2, D-4) and serotonin (5-HT2A, 5-HT2B, 5-HT2c) receptors: Synthesis ofaminomethylbenzo[b]furanones and their evaluation as antipsychotics

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 va lero)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-HT2A, 5-HT2B, 5-HT2C), by neurochemical studies, an d by in vivo assays for antipsychotic potential and the risk of inducing ex trapyramidal side effects. Potency and selectivity depended mainly on the a mine fragment connected to the cyclohexanone structure. Compounds 20b,, wit h a benzoylpiperidine moiety, and 20c, with a benzisoxazolyl fragment, were selective for 5-HT2A receptors. The in vitro and in vivo pharmacological p rofiles of N-[(4-oxo-4,5,6,7-tetrahydrobenzo[b] furan-6-yl)methyl]-4-(p-flu orobenzoyl)piperidine (20b, QF1003B) and N-[(4-oxo-4,5,6,7-tetrahydrobenzo [b] furan-6-yl)methyl] -4-(6-fluorobenzisoxazol-3-yl)piperidine (20c, QF100 4B) suggest that they may be effective as antipsychotic (neuroleptic) drugs .