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), 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 D 3 versus D 2 receptors and does not interact with histamine H 1 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 five-choice serial reaction time procedures. Furthermore, upon either systemic administration (0.04 -2.5 mg/kg s.c.) or introduction into the frontal cortex (0.04 -0.63 g/side), S33138 potently attenuated the perturbation of social recognition by scopolamine or a prolonged intersession 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 prepulse inhibition elicited by apomorphine. In comparison with the above actions, only "high" doses of S33138 (10.0 -40.0 mg/kg s.c.) elicited catalepsy. To summarize, reflecting preferential blockade of D 3 versus D 2 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 with clinically available agents, S33138 displays, thus, a distinctive and promising profile of potential antipsychotic properties.We have recently described a novel benzopyranopyrrolidine derivative, S33138 (Millan et al., 2008a,b) that behaves as a preferential antagonist at cloned, human, and native cerebral dopaminergic D 3 versus D 2 receptors. In addition, it displays modest antagonist properties at serotonin (5-HT) 2A receptors, 5-HT 7 receptors, and ␣ 2C -adrenoceptors (ARs), blockade of which may also be useful in the treatment of schizophrenia Svensson, 2003). In contrast, S33138 does not interact with histamine H 1 , muscarinic, or ␣ 1 -adrenoceptors, antagonism of which provokes cardiovascular-autonomic side effects (Kroeze et al., 2003;Lieberman, 2005). This distinctive receptor-binding profile differentiates S33138 from clinically employed antipsychotics like the neuroleptic and D 2 /D 3 receptor antagonist, haloperidol; the "atypical" agent, clozapine; and two further mulArticle, publication date, and citation information can be found at

Dopamine’s Actions in Primate Prefrontal Cortex: Challenges for Treating Cognitive Disorders

“…D3R antagonists, e.g., S33138, increase catecholamine and acetylcholine efflux in rodent PFC (Lacroix et al, 2003;Millan et al, 2008). S33138 improved working memory and attentional set-shifting performance when given systemically to monkeys with cognitive deficits arising from low-dose MPTP, which causes mild DA depletion (Millan et al, 2010).…”

Repeated antipsychotic treatment progressively potentiates inhibition on phencyclidine-induced hyperlocomotion, but attenuates inhibition on amphetamine-induced hyperlocomotion: Relevance to animal models of antipsychotic drugs

“…In the majority of antipsychotic drug studies using both hyperlocomotion models, the effects of antipsychotic drugs and other experimental drugs are often tested after a single injection and efforts have been devoted to understanding the neurochemical mechanisms underlying amphetamine and phencyclidine-induced behavioral effects and effects of antipsychotics on both types of hyperlocomotion. All antipsychotics acutely inhibit motor activation effect of amphetamine and phencyclidine (Abekawa et al, 2007;Arnt, 1995;Millan et al, 1999Millan et al, , 2008. Antipsychotics with preferential action on D 2 receptors such as haloperidol, fluphenazine, cis(Z)flupentixol, amisulpride, eticlopride, and raclopride all show a preferential inhibitory effect on amphetamine-induced hyperlocomotion over phencyclidine-induced one, whereas atypicals such as clozapine and olanzapine, which are mixed D 2 -like/5-HT 2A antagonists, have an opposite effect, showing a preferential inhibition on phencyclidineinduced hyperlocomotion (Gleason and Shannon, 1997;MaurelRemy et al, 1995;Millan et al, 1999).…”

Synthesis, binding affinity and SAR of new benzolactam derivatives as dopamine D3 receptor ligands

“…13 Another D 3 versus D 2 receptor antagonist is S33138, which is now in Phase IIb clinical trials for schizophrenia. 14 Today there is an urgent need for more selective molecular tools to help definitively separate D 3 actions from those mediated by the D 2 receptors, in order to elucidate the function and potential therapeutic advantages of targeting D 3 receptors.…”