title: Pharmacological profile of MS-377, a novel antipsychotic agent with selective affinity for sigma receptors.
abstract: BACKGROUND
  MS-377 ((R)-(+)-1-(4-chlorophenyl)-3-[4-(2-methoxyethyl)piperazin-1-yl]me thyl-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 vitro assays, radioligand binding assays for sigma 1, sigma 2, D2 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 D2 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 Apo-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 Apo-induced stereotypy and induction of catalepsy in rats.
  
  
  CONCLUSIONS
  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 D2 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.
authors.affiliation: Medicinal Research Department, Mitsui Pharmaceuticals, Inc., Chiba, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Takahashi
authors.forename: K
authors.initials: K
authors.lastname: Sonehara
authors.forename: K
authors.initials: K
authors.lastname: Takagi
authors.forename: T
authors.initials: T
authors.lastname: Miwa
authors.forename: K
authors.initials: K
authors.lastname: Horikomi
authors.forename: N
authors.initials: N
authors.lastname: Mita
authors.forename: H
authors.initials: H
authors.lastname: Nagase
authors.forename: K
authors.initials: K
authors.lastname: Iizuka
authors.forename: K
authors.initials: K
authors.lastname: Sakai
mesh_terms: D000077582:Amisulpride; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001058:Apomorphine / Q000494:pharmacology; D002375:Catalepsy / Q000139:chemically induced; D018491:Dopamine Agonists / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000494:pharmacology; D006168:Guinea Pigs; D006220:Haloperidol / Q000494:pharmacology; D019416:Head Movements / Q000187:drug effects; D008297:Male; D051379:Mice; D010620:Phenazocine / Q000031:analogs & derivatives / Q000494:pharmacology; D010622:Phencyclidine / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology*; D011759:Pyrrolidines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D017448:Receptors, Dopamine D2 / Q000187:drug effects / Q000378:metabolism; D011985:Receptors, Serotonin / Q000187:drug effects / Q000378:metabolism; D017480:Receptors, sigma / Q000187:drug effects / Q000378:metabolism*; D018967:Risperidone / Q000494:pharmacology; D012701:Serotonin / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology; D013239:Stereotyped Behavior / Q000187:drug effects; D013469:Sulpiride / Q000031:analogs & derivatives / Q000494:pharmacology; D013644:Tartrates
chemical_list: C464615:1-(4-chlorophenyl)-3-(4-(2-methoxyethyl) piperazin-1-yl)methyl-2-pyrrolidinone tartrate; D014150:Antipsychotic Agents; D018491:Dopamine Agonists; D016166:Free Radical Scavengers; D010879:Piperazines; D011759:Pyrrolidines; D017448:Receptors, Dopamine D2; D011985:Receptors, Serotonin; D017480:Receptors, sigma; D012702:Serotonin Antagonists; D013644:Tartrates; D012701:Serotonin; C012134:SK&F 10047; D013469:Sulpiride; D000077582:Amisulpride; D010620:Phenazocine; D010622:Phencyclidine; D006220:Haloperidol; D018967:Risperidone; D001058:Apomorphine