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.