title: Neuroprotective effects of the selective type 1 metabotropic glutamate receptor antagonist YM-202074 in rat stroke models.
abstract: We describe in vitro properties and in vivo neuroprotective effects of a newly synthesized, high-affinity, selective allosteric metabotropic glutamate receptor type 1 (mGluR(1)) antagonist, N-cyclohexyl-6-{[(2-methoxyethyl)(methyl)amino]methyl}-N-methylthiazolo[3,2-a]benzimidazole-2-carboxamide (YM-202074). YM-202074 bound an allosteric site of rat mGluR(1) with a K(i) value of 4.8+/-0.37 nM. YM-202074 also inhibited the mGluR(1)-mediated inositol phosphates production in rat cerebellar granule cells with an IC(50) value of 8.6+/-0.9 nM, while showing selectivity over mGluR(2-7). When YM-202074 was infused intravenously at an initial dose of 20 mg/kg/h for 0.5 h followed by a dose of 5 mg/kg/h for 7.5 h, the free concentration of YM-202074 in the brain rapidly (<12 min) reached approximately 0.3 microM, reaching a steady-state phase within 1.5 h. We first treated rats such that they developed transient middle cerebral artery (MCA) occlusion. Results clearly demonstrate a dose-dependent improvement of neurological deficit and reduction of the infarct volume in both the hemisphere and cortex when YM-202074 was infused intravenously immediately after occlusion at a dose of 10 or 20 mg/kg/h for 0.5 h followed by a dose of 2.5 or 5 mg/kg/h for 23.5 h, respectively. Significant neuroprotection was maintained even when the administration of drugs was delayed by up to 2 h following the onset of ischemia. Furthermore, the improvement of neurological deficit and the reduction of infarct volume were sustained for 1 week following the onset of ischemia. These results suggest that YM-202074 exhibits great potential as a novel neuroprotective agent for the treatment of stroke.
authors.affiliation: Pharmacology Research Laboratories, Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, 305-8585, Japan.
authors.forename: Atsuyuki
authors.initials: A
authors.lastname: Kohara
authors.forename: Masayasu
authors.initials: M
authors.lastname: Takahashi
authors.forename: Shin-Ichi
authors.initials: S
authors.lastname: Yatsugi
authors.forename: Seiji
authors.initials: S
authors.lastname: Tamura
authors.forename: Yoshitsugu
authors.initials: Y
authors.lastname: Shitaka
authors.forename: Satoshi
authors.initials: S
authors.lastname: Hayashibe
authors.forename: Shigeki
authors.initials: S
authors.lastname: Kawabata
authors.forename: Masamichi
authors.initials: M
authors.lastname: Okada
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000493:pharmacokinetics / Q000494:pharmacology*; D002545:Brain Ischemia / Q000188:drug therapy* / Q000209:etiology; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D008297:Male; D017551:Microdialysis; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors*; D020521:Stroke / Q000150:complications / Q000188:drug therapy*; D013844:Thiazoles / Q000493:pharmacokinetics / Q000494:pharmacology*; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D001562:Benzimidazoles; C528872:N-cyclohexyl-6-(((2-methoxyethyl)(methyl)amino)methyl)-N-methylthiazolo(3,2-a)benzimidazole-2-carboxamide; D018696:Neuroprotective Agents; D018094:Receptors, Metabotropic Glutamate; D013844:Thiazoles