title: Correlation of receptor occupancy of metabotropic glutamate receptor subtype 1 (mGluR1) in mouse brain with in vivo activity of allosteric mGluR1 antagonists.
abstract: The aim of this study was to clarify the relationship between receptor occupancy and in vivo pharmacological activity of mGluR1 antagonists. The tritiated mGluR1-selective allosteric antagonist [(3)H]FTIDC (4-[1-(2-fluoropyridin-3-yl)-5-methyl-1H-1,2,3-triazol-4-yl]-N-isopropyl-N-methyl-3,6-dihydropyridine-1(2H)-carboxamide) was identified as a radioligand having high affinity for mGluR1-expressing CHO cells (K(D) = 2.1 nM) and mouse cerebellum (K(D) = 3.7 nM). [(3)H]FTIDC bound to mGluR1 was displaced by structurally unrelated allosteric antagonists, suggesting there is a mutual binding pocket shared with different allosteric antagonists. The binding specificity of [(3)H]FTIDC for mGluR1 in brain sections was demonstrated by the lack of significant binding to brain sections prepared from mGluR1-knockout mice. Ex vivo receptor occupancy with [(3)H]FTIDC revealed that the receptor occupancy level by FTIDC correlated well with FTIDC dosage and plasma concentration. Intracerebroventricular administration of (S)-3,5-dihydroxyphenylglycine is known to elicit face washing behavior that is mainly mediated by mGluR1. Inhibition of this behavioral change by FTIDC correlated with the receptor occupancy level of mGluR1 in the brain. A linear relationship between the receptor occupancy and in vivo activity was also demonstrated using structurally diverse mGluR1 antagonists. The receptor occupancy assays could help provide guidelines for selecting appropriate doses of allosteric mGluR1 antagonist for examining the function of mGluR1 in vivo.
authors: Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd., Tsukuba, Ibaraki 300-2611, Japan. gentaroh_suzuki@merck.com
authors: Gentaroh
authors: G
authors: Suzuki
authors: Hiroko
authors: H
authors: Kawagoe-Takaki
authors: Takao
authors: T
authors: Inoue
authors: Toshifumi
authors: T
authors: Kimura
authors: Hirohiko
authors: H
authors: Hikichi
authors: Takashi
authors: T
authors: Murai
authors: Akio
authors: A
authors: Satow
authors: Mikiko
authors: M
authors: Hata
authors: Shunsuke
authors: S
authors: Maehara
authors: Satoru
authors: S
authors: Ito
authors: Hiroshi
authors: H
authors: Kawamoto
authors: Satoshi
authors: S
authors: Ozaki
authors: Hisashi
authors: H
authors: Ohta
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000378:metabolism*; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D011485:Protein Binding; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors* / Q000235:genetics; D011994:Recombinant Proteins / Q000378:metabolism; D012118:Resorcinols / Q000494:pharmacology; D014230:Triazoles / Q000378:metabolism
chemical_list: C521338:4-(1-(2-fluoropyridin-3-yl)-5-methyl-1H-1,2,3,-triazol-4-yl)-N-isopropyl-N-methyl-3,6-dihydropyridine-1(2H)-carboxamide; D018094:Receptors, Metabotropic Glutamate; D011994:Recombinant Proteins; D012118:Resorcinols; D014230:Triazoles; C104077:metabotropic glutamate receptor type 1; C079215:3,5-dihydroxyphenylglycine; D005998:Glycine