Vol. 292, Issue 1, 54-66, January 2000

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 ₁- and ₂-Adrenergic Receptors: II. Functional Profile and a Multiparametric Comparison with Haloperidol, Clozapine, and 11 Other Antipsychotic Agents

Mark J. Millan, Mauricette Brocco, Jean-Michel Rivet, Valérie Audinot, Adrian Newman-Tancredi, Lisa Maiofiss, Sophie Queriaux, Nicole Despaux, Jean-Louis Peglion and Anne Dekeyne

Psychopharmacology Department, Institut de Recherches Servier, Centre de Recherches de Croissy, Paris, Croissy-sur-Seine, France (M.J.M., M.B., J.-M.R., V.A., A.N.-T., A.D.); and Statistics (L.M., S.Q.) and Chemistry B (N.P., J.-L.P.) Departments, Institut de Recherches Servier, Centre de Recherches de Suresnes, Suresnes, France

S18327 was dose-dependently active in several models of potential antipsychotic activity involving dopaminergic hyperactivity: inhibition of apomorphine-induced climbing in mice, of cocaine- and amphetamine-induced hyperlocomotion in rats, and of conditioned avoidance responses in rats. Furthermore, reflecting its high affinity at serotonin_2A sites, S18327 potently blocked phencyclidine-induced locomotion and 1-[2,5-dimethoxy-4-iodophenyl]-2-aminopropane-induced head-twitches in rats. In models of glutamatergic hypoactivity, S18327 blocked hyperlocomotion and spontaneous tail-flicks elicited by the N-methyl-D-aspartate antagonist dizocilpine. The actions of S18327, together with its binding profile at multiple monoaminergic receptors (15 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 clopazine-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 Vogel procedures in rats. Relative to the above paradigms, only markedly (>20-fold) higher doses of S18327 were active in models predictive of potential extrapyramidal side effects: induction of catalepsy and prolactin secretion, and inhibition of methylphenidate-induced gnawing in rats. S18327 showed only modest affinity for histaminic and muscarinic receptors. Multiparametric analysis of these data distinguished S18327 from both haloperidol (high extrapyramidal potential) and clozapine (high histaminic and muscarinic affinity). In conclusion, S18327 displays a broad-based pattern of potential antipsychotic activity at doses appreciably lower than those eliciting extrapyramidal side effects. In this respect, S18327 closely resembles clozapine, but it is chemically distinct and displays weak affinity for histaminic and muscarinic receptors.