Pharmacological profile of MS-377, a novel antipsychotic agent with selective affinity for σ receptors

Rationale: MS-377 ((R)-(+)-1-(4-chlorophenyl)-3-[4-(2-methoxyethyl)piperazin- -1-yl]methyl-2-pyrrolidinone L-tartrate) was discovered as a new chemical entity with affinity for sigma receptors and without affinities for dopamine receptors. Objective: In the present study, we examined the antipsychotic profile of MS-377 in several in vitro and in vivo experiments. Methods: As in vit re assays, radioligand binding assays for sigma(1), sigma(2), D-2 and 5-HT2 receptors were performed. As in vivo animal models, the effects of MS-377 on several behavioral models induced by phencyclidine (PCP), (+)-N-allylnormetazocine (NANM), apomorphine (Apo) and 5-hydroxytryptamine (5-HTP) were evaluated. All assay systems were conducted using the clinically active antipsychotic agents as reference standards. Results: MS-377 displaced ligand bound to sigma(1) receptors in vitro. However, no such displacement was observed at sigma(2) or 5-HT2 receptors in vitro, or at D-2 receptors either in vitro or in vivo. In behavioral studies, MS-377 inhibited both NANM- and PCP-induced head-weaving at low doses in mice and rats, whereas antipsychotic agents used in the present study were only effective against NANM-induced head-weaving behavior in mice. In addition, MS-377 antagonized Ape-induced climbing behavior and 5-HTP-induced head-twitching behavior in mice. MS-377 was inactive in models of extrapyramidal side effect (EPS) liability such as prevention of Ape-induced stereotypy and induction of catalepsy in rats. Conclusion: The present study demonstrated that MS-377 had not only anti-PCP activity but also anti-dopaminergic and anti-serotonergic activities in vivo, without acting directly through D-2 or 5-HT2 receptors. Therefore, MS-377 could be a novel antipsychotic agent with clinical efficacy for overall symptoms of schizophrenia including its negative symptoms and without EPS liability.