Antipsychotic profiles of TASP0443294, a novel and orally active positive allosteric modulator of metabotropic glutamate 2 receptor.

Abstract

Glutamatergic dysfunction has been implicated in psychiatric disorders such as schizophrenia. The stimulation of metabotropic glutamate (mGlu) 2 receptor has been shown to be effective in a number of animal models of schizophrenia. In this study, we investigated the antipsychotic profiles of (2S)-5-methyl-2-{[4-(1,1,1-trifluoro-2-methylpropan-2-yl)phenoxy]methyl}-2,3-dihydroimidazo[2,1-b][1,3]oxazole-6-carboxamide (TASP0443294), a newly synthesized positive allosteric modulator of the mGlu2 receptor. TASP0443294 potentiated the response of human mGlu2 and rat mGlu2 receptors to glutamate with EC50 values of 277 and 149 nM, respectively, without affecting the glutamate response of human mGlu3 receptor. TASP0443294 was distributed in the brain and cerebrospinal fluid after peroral administration in rats. The peroral administration of TASP0443294 inhibited methamphetamine-induced hyperlocomotion in rats, which was attenuated by an mGlu2/3 receptor antagonist, and improved social memory impairment induced by 5R,10S-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen maleate (MK-801) in rats. Furthermore, TASP0443294 reduced the ketamine-induced basal gamma hyperactivity in the prefrontal cortex and suppressed rapid eye movement (REM) sleep in rats. These findings indicate that TASP0443294 is an mGlu2 receptor positive allosteric modulator with antipsychotic activity, and that the suppression of aberrant gamma oscillations and REM sleep could be considered as neurophysiological biomarkers for TASP0443294.

• Authors: Hirohiko Hikichi, Tetsuaki Hiyoshi, Toshiyuki Marumo, Yasumitsu Tomishima, Ayaka Kaku, Izumi Iida, Hiroki Urabe, Tomoko Tamita, Akito Yasuhara, Jun-ichi Karasawa, Shigeyuki Chaki
• Journal: Journal of pharmacological sciences (J Pharmacol Sci) Vol. 127 Issue 3 Pg. 352-61 (Mar 2015) ISSN: 1347-8648 [Electronic] Japan
• PMID: 25837934 (Publication Type: Journal Article)
• Copyright: Copyright © 2015 Japanese Pharmacological Society. Production and hosting by Elsevier B.V. All rights reserved.

Chemical References

• Antipsychotic Agents
• Imidazoles
• Oxazoles
• Receptors, Metabotropic Glutamate
• TASP0443294
• metabotropic glutamate receptor 2

Topics

• Administration, Oral
• Allosteric Regulation (drug effects)
• Animals
• Antipsychotic Agents (administration & dosage, pharmacokinetics, pharmacology)
• Cells, Cultured
• Disease Models, Animal
• Electroencephalography (drug effects)
• Humans
• Imidazoles (administration & dosage, pharmacokinetics, pharmacology)
• Male
• Motor Activity (drug effects)
• Oxazoles (administration & dosage, pharmacokinetics, pharmacology)
• Prefrontal Cortex (drug effects)
• Rats, Sprague-Dawley
• Rats, Wistar
• Receptors, Metabotropic Glutamate (metabolism)
• Schizophrenia (drug therapy, genetics)
• Sleep, REM (drug effects)
• Stimulation, Chemical