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

Abstract

RATIONALE:

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.

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 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: S Takahashi, K Sonehara, K Takagi, T Miwa, K Horikomi, N Mita, H Nagase, K Iizuka, K Sakai
• Journal: Psychopharmacology (Psychopharmacology (Berl)) Vol. 145 Issue 3 Pg. 295-302 (Aug 1999) ISSN: 0033-3158 [Print] Germany
• PMID: 10494578 (Publication Type: Comparative Study, Journal Article)

Chemical References

• 1-(4-chlorophenyl)-3-(4-(2-methoxyethyl) piperazin-1-yl)methyl-2-pyrrolidinone tartrate
• Antipsychotic Agents
• Dopamine Agonists
• Free Radical Scavengers
• Piperazines
• Pyrrolidines
• Receptors, Dopamine D2
• Receptors, Serotonin
• Receptors, sigma
• Serotonin Antagonists
• Tartrates
• Serotonin
• SK&F 10047
• Sulpiride
• Amisulpride
• Phenazocine
• Phencyclidine
• Haloperidol
• Risperidone
• Apomorphine

Topics

• Amisulpride
• Animals
• Antipsychotic Agents (pharmacology)
• Apomorphine (pharmacology)
• Catalepsy (chemically induced)
• Dopamine Agonists (pharmacology)
• Free Radical Scavengers (pharmacology)
• Guinea Pigs
• Haloperidol (pharmacology)
• Head Movements (drug effects)
• Male
• Mice
• Phenazocine (analogs & derivatives, pharmacology)
• Phencyclidine (pharmacology)
• Piperazines (pharmacology)
• Pyrrolidines (pharmacology)
• Rats
• Rats, Wistar
• Receptors, Dopamine D2 (drug effects, metabolism)
• Receptors, Serotonin (drug effects, metabolism)
• Receptors, sigma (drug effects, metabolism)
• Risperidone (pharmacology)
• Serotonin (pharmacology)
• Serotonin Antagonists (pharmacology)
• Stereotyped Behavior (drug effects)
• Sulpiride (analogs & derivatives, pharmacology)
• Tartrates