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.