JL13, a clozapine-like potential antipsychotic agent, reduces sympathetic cutaneous vasomotor alerting responses (SCVARs) in rats, but the drug is less potent than clozapine

Clozapine is an atypical antipsychotic drug used to treat schizophrenia. However clozapine has serious side effects and there is a search for new antipyschotics. One such agent is JL13 [5-(4-methylpiperazin-1-yl)-8-chloro-pyrido[2,3-b][1,5] benzoxazepine fumarate], structurally related to clozapine but postulated to have less haematological and cardiological side effects because of reduced sensitivity to oxidation. Clozapine reduces SCVARs in rats. We have evaluated JL13 in this model. Sprague Dawley rats (250–450 g) were instrumented (Fluothane anesthesia) with Doppler blood flow probe at the base of the tail artery and the effect of JL13 (0.0625–5 mg/kg s.c.) on SCVARs (1) was evaluated in the conscious freely moving animal. JL13 significantly reduced SCVARs, (linear regression between log dose and SCVAR index P<0.001, R2=0.60, n=6 rats at each dose). Prior blockade of dopamine D2 receptors with spiperone (25 μg/kg) did not reduce the effect of JL13. Comparison with previous results (1) indicates that the SCVAR-reducing action of JL13 is only approximately one-fifth as potent as clozapine, and dopamine D2 stimulation does not contribute to the action of JL13. Supported by NHMRC.