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

Journal of Pharmacological Sciences

Tomoko Tamita¹  Hiroki Urabe¹  Akito Yasuhara¹  Izumi Iida²  Hirohiko Hikichi³  Yasumitsu Tomishima³  Shigeyuki Chaki³  Tetsuaki Hiyoshi³  Toshiyuki Marumo³  Ayaka Kaku³  Jun-ichi Karasawa³ 

[1] Chemistry Laboratories, Taisho Pharmaceutical Co., Ltd., 1-403 Yoshino-cho, Kita-ku, Saitama, Saitama 331-9530, Japan;Drug Safety and Pharmacokinetics Laboratories, Taisho Pharmaceutical Co., Ltd., 1-403 Yoshino-cho, Kita-ku, Saitama, Saitama 331-9530, Japan;Pharmacology Laboratories, Taisho Pharmaceutical Co., Ltd., 1-403 Yoshino-cho, Kita-ku, Saitama, Saitama 331-9530, Japan;

关键词: TASP0443294;    mGlu2 receptor positive allosteric modulator;    Hyperlocomotion;    Social memory;    EEG;   

DOI  :  10.1016/j.jphs.2015.02.004

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown