Received for publication November 20, 2007.
Revised December 19, 2007.
Accepted for publication December 19, 2007.

S33138, A PREFERENTIAL DOPAMINE D3 VERSUS D2 RECEPTOR ANTAGONIST AND POTENTIAL ANTIPSYCHOTIC AGENT. III. ACTIONS IN MODELS OF THERAPEUTIC ACTIVITY AND INDUCTION OF SIDE-EFFECTS

Abstract

In contrast to clinically-available antipsychotics, the novel benzopyranopyrrolidine derivative, S33138 (N-[4-[2-[(3aS,9bR)-8-cyano-1,3a,4,9b-tetrahydro[1]benzopyrano[3,4-c]pyrrol-2(3H)-yl)-ethyl]phenyl-acetamide), behaves as a preferential antagonist of D₃ vs D₂ receptors and does not interact with histamine H₁ and muscarinic receptors. In contrast to haloperidol, clozapine, olanzapine and risperidone, S33138 (0.16-2.5 mg/kg, s.c.) did not disrupt performance in passive-avoidance and 5 choice serial reaction time procedures. Further, upon either systemic administration (0.04-2.5 mg/kg, s.c.) or introduction into the frontal cortex (0.04-0.63 µg/side), S33138 potently attenuated the perturbation of social recognition by scopolamine or a prolonged inter-session delay. Over a comparable and low dose-range, S33138 (0.04-0.63 mg/kg, s.c.) elevated dialysis levels of acetylcholine in the frontal cortex of freely-moving rats. At higher doses (2.5-10.0 mg/kg, s.c.), S33138 also increased frontocortical levels of histamine, whereas monoamines, glutamate, glycine and GABA were unaffected. By analogy to the other antipsychotics, S33138 (0.63-10.0 mg/kg, s.c.) inhibited conditioned avoidance responses in rats, apomorphine-induced climbing in mice, and hyperlocomotion elicited by amphetamine, cocaine, dizocilpine, ketamine and phencyclidine in rats. S33138 (0.16-2.5 mg/kg, s.c.) also blocked the reduction of pre-pulse inhibition elicited by apomorphine. In comparison to the above actions, only "high" doses of S33138 (10.0-40.0 mg/kg, s.c.) elicited catalepsy. To summarize, reflecting preferential blockade of D₃ vs D₂ receptors, S33138 preserves and/or enhances cognitive function, increases frontocortical cholinergic transmission and is active in models of antipsychotic properties at doses well below those inducing catalepsy. In comparison to clinically-available agents, S33138 displays, thus, a distinctive and promising profile of potential antipsychotic properties.

Key words: D3 receptor, antipsychotics, clozapine, cognition, dopamine, schizophrenia