Antipsychotic/σ-receptor Antagonist: Novel Cycloalkylpiperidines as Antipsychotics and Antidotes to Psychomimetics

Summary

Novelty: Cycloalkylpiperidines are disclosed as potential antipsychotic (anti-aggressive and antihallucinogenic) agents. The compounds are potent and selective σ-receptor antagonists with poor affinity for the D₂ dopamine receptor and should therefore show few dyskinesic side-effects, associated with classical antipsychotic agents.

Biology: Competition binding data in guinea pig striatal membranes against [³H]-SKF10047 (σ-receptor selective) and [³H]-spiroperidol (D₂ dopamine receptor selective) demonstrate the high selectivity of the compounds for the σ-receptor although no individual values are given. In vivo tests indicate that the compounds may reduce isolation-induced aggression (mice) and PCP-induced turning behaviour (rats), indicative of anti-aggressive and antihallucinogenic activity. The failure to induce catalepsy in rats indicates reduced dyskinesic side-effects.

Chemistry: The synthesis of the compounds is outlined in twelve schemes which, together with selected intermediates, forms a subsidiary part of the claim. Five hundred and fifty-seven examples are given with eleven compounds especially preferred, including 1-(cyclopropylmethyl)-4-(2′-(4″-fluorophenyl)-2′-oxoethyl)-piperidine.