Vol. 298, Issue 1, 386-391, July 2001

Effects of JL13, a Pyridobenzoxazepine with Potential Atypical Antipsychotic Activity, in Animal Models for Schizophrenia

Bart A. Ellenbroek, Jean-François Liégeois, Jacques Bruhwyler and Alexander R. Cools

Department of Psychoneuropharmacology, University of Nijmegen, The Netherlands (B.A.E., A.R.C.); Laboratory of Medicinal Chemistry, University of Liège, Liège, Belgium (J.-F.L.); and Therabel Research s.a., Brussels, Belgium (J.B.)

JL13 [5-(4-methylpiperazin-1-yl)-8-chloro-pyrido[2,3-b][1,5] benzoxazepine fumarate] is a substance with a close structural resemblance to clozapine. However, it is less sensitive to oxidation and may therefore have less hematological side effects. In the present study, JL13 was compared with clozapine and haloperidol in several animal models for schizophrenia. The paw test represents a screening model for antipsychotic drugs that can discriminate between drugs with extrapyramidal side effects and drugs without. Haloperidol increased both forelimb retraction time and hindlimb retraction time (HRT), whereas both clozapine and JL13 increased only HRT. In the prepulse inhibition paradigm, all three drugs reversed the apomorphine- and the amphetamine-induced disruption of prepulse inhibition. However, whereas haloperidol was equally effective against both dopaminergic drugs, JL13 and clozapine were more effective against amphetamine. Finally, only JL13 was able to increase prepulse inhibition in normal rats, whereas only clozapine reduced basal startle amplitude. Taken together, these data suggest that JL13 may be an effective antipsychotic drug, with a profile similar to clozapine.