The preclinical antipsychotic evaluation of HRP 913, a novel benzisoxazole derivative

Abstract

AbstractHRP 913 {1‐[3‐(6‐fluoro‐1,2‐benzisoxazole‐3‐yl)propyl]‐4‐(2‐oxo‐1‐benzimidazolinyl)} piperidine demonstrated preclinical antipsychotic activity with features that may provide a clinical advantage over current therapy. It was effective in blocking amphetamine stereotypy in rats (ED50 = 0.4 mg/kg, i.p.), amphetamine circling in SN‐lesioned rats (ED50 = 0.3 mg/kg, i.p.), apomorphine stereotypy in rats (ED50 = 0.8 mg/kg, i.p.), but not apomorphine circling in SN‐lesioned rats (up to 10 mg/kg, i.p.). It also blocked Sidman avoidance in rats (ED50 = 0.17 mg/kg, i.p.) and monkeys (ED50 = 0.2 mg/kg, p.o.) and blocked intracranial self‐stimulation in rats (0.09 mg/kg, i.p.). A unique biphasic effect on catalepsy was found. Monkey EPS studies demonstrate a potential for EPS that is lower than some existing clinical standards. HRP 913 displaced 3H‐spiroperidol from rat striatal sites (IC50 = 6.0 × 10−9 M) and inhibited WB‐4101 binding (IC50 = 2.6 × 10−8 M) with only slight effect on QNB binding. HRP 913 does not appear to have marked α‐blocking properties in vivo. HRP 913 is a potent dopamine antagonist and is predicted to have less side effects than current therapy.