SYNTHESIS AND ATYPICAL ANTIPSYCHOTIC PROFILE OF SOME 2-(2-PIPERIDINOETHYL)BENZOCYCLOALKANONES AS ANALOGS OF BUTYROPHENONE

Four new 2-(2-piperidinoethyl)benzocycloalkanone derivatives, 20-23, were prepared and evaluated as potential antipsychotic agents in receptor binding assays for dopamine (DA) and 5-HT2A receptors and in functional and behavioral screens. Their affinities for D-2 receptors (K-i's in the nanomolar range: 46.7-70.7) and D-1 receptors (K-i's in the micromolar range: 1.09-2.81) were slightly lower than that showed by haloperidol (K-i's in the nanomolar range: 5.01 and 97.72 for D-2 and for D-1 receptors, respectively). The ratio of pK(i)'s values D-1/D-2 showed that the new molecules are more D-2-selective than haloperidol. In contrast, in the [H-3]-ketanserin binding assays the new compounds had greater affinity for 5-HT2A receptors (pK(i)'s 7.89-8.60) than haloperidol (pKi 7.70) and in functional studies, endothelium-stripped aorta rings, the pA(2) values (6.75-8.12) were slightly lower than that of ketanserin (8.87) in suppresing serotonin-induced contractions. The pK(i)'s for D-2 binding (and to a lesser extent pK(i)'s for D-1 binding) tend to be greater among typical (classical) than among atypical antipsychotics, while these two classes of antipsychotics exhibit no difference with regard to pK(i)'s for 5-HT2A receptors. The ratios of pK(i)'s for 5-HT2A/D-2 receptors may be useful for rapid screening of new compounds, and its potential induction of extrapyramidal symptoms (ratio values > 1.12 were predictive of an atypical antipsychotic profile). The new molecules had a ratio value in the range 1.08-1.20, while haloperidol showed a ratio of 0.93. In the behavioral screening tests, the new molecules showed antagonist activity of amphetamine-inducing hyperactivity and apomorphine-induced climbing (predictive tests for antipsychotic activity). In the catalepsy test (predictive test for induction of extrapyramidal symptoms), the values obtained were in accordance with an atypical antipsychotic drugs profile.