S18327 (1-{2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperid-1-yl]ethyl}3-phenyl imidazolin-2-one), a novel, potential antipsychotic displaying marked antagonist properties at alpha(1) and alpha(2)-adrenergic receptors: II. Functional profile and a multiparametric comparison with haloperidol, clozapine,and 11 other antipsychotic agents

S18327 was dose-dependently active in several models of potential antipsych otic activity involving dopaminergic hyperactivity: inhibition of apomorphi ne-induced climbing in mice, of cocaine- and amphetamine-induced hyperlocom otion in rats, and of conditioned avoidance responses in rats. Furthermore, reflecting its high affinity at serotonin(2A) sites, S18327 potently block ed phencyclidine-induced locomotion and 1-[ 2,5-dimethoxy-4-iodophenyl]- 2- aminopropane-induced head-twitches in rats. In models of glutamatergic hypo activity, S18327 blocked hyperlocomotion and spontaneous tail-flicks elicit ed by the N-methyl-D-aspartate antagonist dizocilpine. The actions of S1832 7, together with its binding profile at multiple monoaminergic receptors (1 5 parameters in total), were compared with those of clozapine, haloperidol, and 11 other antipsychotics by multiparametric analysis, and the resulting dendrogram positioned S18327 close to clozapine. Consistent with a clopazi ne-like profile, S18327 generalized to a clozapine discriminative stimulus and evoked latent inhibition in rats, blocked aggression in isolated mice, and displayed anxiolytic properties in the ultrasonic vocalization and Voge l procedures in rats. Relative to the above paradigms, only markedly (>20-f old) higher doses of S18327 were active in models predictive of potential e xtrapyramidal side effects: induction of catalepsy and prolactin secretion, and inhibition of methylphenidate-induced gnawing in rats. S18327 showed o nly modest affinity for histaminic and muscarinic receptors. Multiparametri c analysis of these data distinguished S18327 from both haloperidol (high e xtrapyramidal potential) and clozapine (high histaminic and muscarinic affi nity). In conclusion, S18327 displays a broad-based pattern of potential an tipsychotic activity at doses appreciably lower than those eliciting extrap yramidal side effects. In this respect, S18327 closely resembles clozapine, but it is chemically distinct and displays weak affinity for histaminic an d muscarinic receptors.