RT Journal Article
SR Electronic
T1 Neurophysiologic and Antipsychotic Profiles of TASP0433864, a Novel Positive Allosteric Modulator of Metabotropic Glutamate 2 Receptor
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 642
OP 653
DO 10.1124/jpet.114.218651
VO 351
IS 3
A1 Tetsuaki Hiyoshi
A1 Toshiyuki Marumo
A1 Hirohiko Hikichi
A1 Yasumitsu Tomishima
A1 Hiroki Urabe
A1 Tomoko Tamita
A1 Izumi Iida
A1 Akito Yasuhara
A1 Jun-ichi Karasawa
A1 Shigeyuki Chaki
YR 2014
UL http://jpet.aspetjournals.org/content/351/3/642.abstract
AB Excess glutamatergic neurotransmission has been implicated in the pathophysiology of schizophrenia, and the activation of metabotropic glutamate 2 (mGlu2) receptor may exert antipsychotic effects by normalizing glutamate transmission. In the present study, we investigated the neurophysiologic and antipsychotic profiles of TASP0433864 [(2S)-2-[(4-tert-butylphenoxy)methyl]-5-methyl-2,3-dihydroimidazo[2,1-b][1,3]oxazole-6-carboxamide], a newly synthesized positive allosteric modulator (PAM) of mGlu2 receptor. TASP0433864 exhibited PAM activity at human and rat mGlu2 receptors with EC50 values of 199 and 206 nM, respectively, without exerting agonist activity at rat mGlu2 receptor. TASP0433864 produced a leftward and upward shift in the concentration-response curve of glutamate-increased guanosine 5′-O-(3-[35S]thio)triphosphate binding to mGlu2 receptor. In contrast, TASP0433864 had negligible activities for other mGlu receptors, including mGlu3 receptor, and did not have any affinity for other receptors or transporters. In hippocampal slices, TASP0433864 potentiated an inhibitory effect of DCG-IV [(2S,2′R,3′R)-2-(2′,3′-dicarboxylcyclopropyl)glycine], a mGlu2/3 receptor agonist, on the field excitatory postsynaptic potentials in the dentate gyrus, indicating that TASP0433864 potentiates the mGlu2 receptor–mediated presynaptic inhibition of glutamate release. Moreover, TASP0433864 inhibited both MK-801 [(5S,10R)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen maleate]- and ketamine-increased cortical γ band oscillation in the rat cortical electroencephalogram, which have been considered to reflect the excess activation of cortical pyramidal neurons. The inhibitory effect of TASP0433864 on cortical activation was also observed in the mouse 2-deoxy-glucose uptake study. In a behavioral study, TASP0433864 significantly inhibited both ketamine- and methamphetamine-increased locomotor activities in mice and rats, respectively. Collectively, these findings indicate that TASP0433864 is a selective mGlu2 receptor PAM with antipsychotic activity, and the attenuation of excess glutamatergic neurotransmission may be involved in the action of TASP0433864.