THE DISCOVERY AND STRUCTURE-ACTIVITY-RELATIONSHIPS OF YDRO-4-PHENYL-1-[(ARYLCYCLOHEXENYL)ALKYL]PYRIDINES - DOPAMINE AUTORECEPTOR AGONISTS AND POTENTIAL ANTIPSYCHOTIC AGENTS

A novel dopamine (DA) autoreceptor agonist, 1,2,3,6-tetrahydro-4-pheny l-1-[(3-phenyl cyclohexen-1-yl)methyl]pyridine (14), was identified. T he structure-activity relationships surrounding this compound were stu died by synthesis of analogues and evaluation of their dopaminergic ac tivity. The cyclohexene substitution pattern was varied along with the length of the chain connecting the 1,2,3,6-tetrahydro-4-phenylpyridin e to the cyclohexene. Compound 14, having the 1,3-substitution pattern and a single methylene chain, was the most potent. The 1,2,3,6-tetrah ydro-4-phenylpyridine could be replaced by other aryl-cyclic amines wi th a slight loss in activity. The phenyl group on the cyclohexene ring could be para substituted; electron-donating groups were better toler ated than electron-withdrawing groups. Finally, the enantiomers of 14 were resolved via the 1,1'-binaphthy-2,2'-diyl hydrogen phosphate salt s. Although both isomers were partial DA agonists, the (+)-enantiomer had higher intrinsic activity than the (-)-enantiomer. Syntheses were developed that allowed rapid preparation of analogues. An X-ray crysta l structure determination of an intermediate identified the (+)isomer of 14 as having R configuration. This compound, designated CI-1007 (PD 143188), was found to have antipsychotic-like activity in behavioral tests; in particular, it was orally active in the conditioned avoidanc e test in squirrel monkeys with an ED(50) of 0.6 mg/kg. The overall pr ofile suggests that (R)-(+)-14 may be a clinically useful antipsychoti c agent.