title: Neurophysiologic and antipsychotic profiles of TASP0433864, a novel positive allosteric modulator of metabotropic glutamate 2 receptor.
abstract: 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-[(35)S]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.
authors.affiliation: Pharmacology Laboratories (T.H., T.M., H.H., Y.T., J.K., S.C.), Chemistry Laboratories (H.U., T.T., A.Y.), and Drug Safety and Pharmacokinetics Laboratories (I.I.), Taisho Pharmaceutical Co., Ltd., Saitama, Japan t-hiyoshi@so.taisho.co.jp.
authors.forename: Tetsuaki
authors.initials: T
authors.lastname: Hiyoshi
authors.affiliation: Pharmacology Laboratories (T.H., T.M., H.H., Y.T., J.K., S.C.), Chemistry Laboratories (H.U., T.T., A.Y.), and Drug Safety and Pharmacokinetics Laboratories (I.I.), Taisho Pharmaceutical Co., Ltd., Saitama, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Marumo
authors.affiliation: Pharmacology Laboratories (T.H., T.M., H.H., Y.T., J.K., S.C.), Chemistry Laboratories (H.U., T.T., A.Y.), and Drug Safety and Pharmacokinetics Laboratories (I.I.), Taisho Pharmaceutical Co., Ltd., Saitama, Japan.
authors.forename: Hirohiko
authors.initials: H
authors.lastname: Hikichi
authors.affiliation: Pharmacology Laboratories (T.H., T.M., H.H., Y.T., J.K., S.C.), Chemistry Laboratories (H.U., T.T., A.Y.), and Drug Safety and Pharmacokinetics Laboratories (I.I.), Taisho Pharmaceutical Co., Ltd., Saitama, Japan.
authors.forename: Yasumitsu
authors.initials: Y
authors.lastname: Tomishima
authors.affiliation: Pharmacology Laboratories (T.H., T.M., H.H., Y.T., J.K., S.C.), Chemistry Laboratories (H.U., T.T., A.Y.), and Drug Safety and Pharmacokinetics Laboratories (I.I.), Taisho Pharmaceutical Co., Ltd., Saitama, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Urabe
authors.affiliation: Pharmacology Laboratories (T.H., T.M., H.H., Y.T., J.K., S.C.), Chemistry Laboratories (H.U., T.T., A.Y.), and Drug Safety and Pharmacokinetics Laboratories (I.I.), Taisho Pharmaceutical Co., Ltd., Saitama, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Tamita
authors.affiliation: Pharmacology Laboratories (T.H., T.M., H.H., Y.T., J.K., S.C.), Chemistry Laboratories (H.U., T.T., A.Y.), and Drug Safety and Pharmacokinetics Laboratories (I.I.), Taisho Pharmaceutical Co., Ltd., Saitama, Japan.
authors.forename: Izumi
authors.initials: I
authors.lastname: Iida
authors.affiliation: Pharmacology Laboratories (T.H., T.M., H.H., Y.T., J.K., S.C.), Chemistry Laboratories (H.U., T.T., A.Y.), and Drug Safety and Pharmacokinetics Laboratories (I.I.), Taisho Pharmaceutical Co., Ltd., Saitama, Japan.
authors.forename: Akito
authors.initials: A
authors.lastname: Yasuhara
authors.affiliation: Pharmacology Laboratories (T.H., T.M., H.H., Y.T., J.K., S.C.), Chemistry Laboratories (H.U., T.T., A.Y.), and Drug Safety and Pharmacokinetics Laboratories (I.I.), Taisho Pharmaceutical Co., Ltd., Saitama, Japan.
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Karasawa
authors.affiliation: Pharmacology Laboratories (T.H., T.M., H.H., Y.T., J.K., S.C.), Chemistry Laboratories (H.U., T.T., A.Y.), and Drug Safety and Pharmacokinetics Laboratories (I.I.), Taisho Pharmaceutical Co., Ltd., Saitama, Japan.
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Chaki
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects / Q000502:physiology; D000818:Animals; D014150:Antipsychotic Agents / Q000737:chemistry* / Q000494:pharmacology*; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007093:Imidazoles / Q000737:chemistry* / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009924:Organ Culture Techniques; D010080:Oxazoles / Q000737:chemistry* / Q000494:pharmacology*; D011485:Protein Binding / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists* / Q000502:physiology*
chemical_list: C000595260:2-((4-tert-butylphenoxy)methyl)-5-methyl-2,3-dihydroimidazo(2,1-b)(1,3)oxazole-6-carboxamide; D014150:Antipsychotic Agents; D007093:Imidazoles; D010080:Oxazoles; D018094:Receptors, Metabotropic Glutamate; C108822:metabotropic glutamate receptor 2