Pharmacological profile of MS-377, a novel antipsychotic agent with selective affinity for sigma receptors
| Autor: | K Takagi, K Sakai, Naruyoshi Mita, K Iizuka, T Miwa, Hiroshi Nagase, S Takahashi, K Horikomi, K Sonehara |
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| Rok vydání: | 1999 |
| Předmět: |
Male
medicine.medical_specialty Serotonin Pyrrolidines Apomorphine Guinea Pigs Phencyclidine Pharmacology Piperazines chemistry.chemical_compound Mice Antipsychotic Agent Phenazocine In vivo Dopamine receptor D2 Internal medicine Haloperidol medicine Animals Receptors sigma Rats Wistar Receptor Tartrates Catalepsy Receptors Dopamine D2 Free Radical Scavengers Risperidone Rats Endocrinology chemistry Dopamine receptor Sultopride Head Movements Receptors Serotonin Dopamine Agonists Serotonin Antagonists Amisulpride Stereotyped Behavior Sulpiride medicine.drug Antipsychotic Agents |
| Zdroj: | Psychopharmacology. 145(3) |
| ISSN: | 0033-3158 |
| Popis: | 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 σ 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 σ1, σ2, 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 σ1 receptors in vitro. However, no such displacement was observed at σ2 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. |
| Databáze: | OpenAIRE |
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