Conformationally constrained butyrophenones with mixed dopaminergic (D(2)) and serotoninergic (5-HT(2A), 5-HT(2C)) affinities: synthesis, pharmacology, 3D-QSAR, and molecular modeling of (aminoalkyl)benzo- and -thienocycloalkanones as putative atypical antipsychotics.

A series of novel conformationally restricted butyrophenones (2- (aminoethyl)- and 3-(aminomethyl)thieno- or benzocycloalkanones bearing (6- fluorobenzisoxazolyl)piperidine, (p-fluorobenzoyl)piperidine, (o- methoxyphenyl)piperazine, or linear butyrophenone fragments) were prepared and evaluated as atypical antipsychotic agents by in vitro assays of affinity for dopamine receptors (D1, D2) and serotonin receptors (5-HT2(A), 5- HT2(C)) and by in vivo assays of antipsychotic potential and the risk of inducing extrapyramidal side effects. Potency and selectivity depended mainly on the amine fragment connected to the cycloalkanone structure. As a group, compounds with a benzisoxazolyl fragment had the highest 5-HT2(A) activities, followed by the benzoylpiperidine derivatives; in general, α- substituted cycloalkanone derivatives were more active than the corresponding β-substituted congeners. CoMFA (comparative molecular field analysis) and docking studies showed electrostatic, steric, and lipophilic determinants of 5-HT2(A) and D2 affinities and 5-HT2(A)/D2 selectivity. The in vitro and in vivo pharmacological profiles of N-[(4-oxo-4H-5,6- dihydrocyclopenta[b]thiophene-5-yl)ethyl]-4-(6-fluorobenzisoxazol-3- yl)piperidine (23b, QF 0510B), N-[(4-oxo-4,5,6,7- tetrahydrobenzo[b]thiophene-5-yl)ethyl]-4-(6-fluorobenzisoxazol-3- yl)piperidine (24b, QF 0610B), and N-[(7-oxo-4,5,6,7- tetrahydrobenzo[b]thiophene-6-yl)ethyl]4-(6-fluorobenzisoxazol-3- yl)piperidine (29b, QF 0902B) suggest that they may be effective antipsychotic drugs with low propensity to induce extrapyramidal side effects.