Conformationally constrained butyrophenones with mixed dopaminergic (D-2) and serotoninergic (5-HT2A, 5-HT2C) 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-fluorobenzi soxazolyl)piperidine, (p-fluorobenzoyl)piperidine, (o-methoxyphenyl)piperaz ine, or linear butyrophenone fragments) were prepared and evaluated as atyp ical antipsychotic agents by in vitro assays of affinity for dopamine recep tors (D-1, D-2) and serotonin receptors (5-HT2A 5-HT2C) and by in vivo assa ys of antipsychotic potential and the risk of inducing extrapyramidal side effects. Potency and selectivity depended mainly on the amine fragment conn ected to the cycloalkanone structure. As a group, compounds with a benzisox azolyl fragment had the highest 5-HT2A activities, followed by the benzoylp iperidine derivatives; in general, alpha-substituted cycloalkanone derivati ves were more active than the corresponding beta-substituted congeners. CoM FA (comparative molecular field analysis) and docking studies showed electr ostatic, steric, and lipophilic determinants of 5-HT2A and D-2 affinities a nd 5-HT2A/D-2 selectivity. The in vitro and in vivo pharmacological profile s of N-[(4-oxo-4H-5,6-dihydrocyclopenta[b]thiophene-5-yl)ethyl]-4-(6-fluoro benzisoxazol-3-yl)piperidine (23b, QF 0510B), N-[(4-oxo-4,5,6,7-tetrahydrob enzo[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 extrapyrami dal side effects.