Pharmacological effects of the metabotropic glutamate receptor 1 antagonist compared with those of the metabotropic glutamate receptor 5 antagonist and metabotropic glutamate receptor 2/3 agonist in rodents: detailed investigations with a selective allosteric metabotropic glutamate receptor 1 antagonist, FTIDC [4-[1-(2-fluoropyridine-3-yl)-5-methyl-1H-1,2,3-triazol-4-yl]-N-isopropyl-N-methyl-3,6-dihydropyridine-1(2H)-carboxamide].
The functional roles of metabotropic glutamate receptor (mGluR) 1 in integrative brain functions were investigated using a potent and selective mGluR1 allosteric antagonist, FTIDC [4-[1-(2-fluoropyridine-3-yl)-5-methyl-1H-1,2,3-triazol-4-yl]-N-isopropyl-N-methyl-3,6-dihydropyridine-1(2H)-carboxamide], in comparison with the mGluR5 allosteric antagonist and the mGluR2/3 orthosteric agonist in rodents. FTIDC reduced maternal separation-induced ultrasonic vocalization and stress-induced hyperthermia without affecting behaviors in the elevated plus maze. An mGluR5 antagonist, 2-methyl-6-(phenylethynyl)-pyridine (MPEP), and an mGluR2/3 agonist, LY379268 [(1R,4R,5S,6R)-4-amino-2-oxabicyclo[3.1.0]hexane-4,6-dicarboxylic acid], showed anxiolytic activities in these models, suggesting involvement of postsynaptic mGluR1 in stress-related responses comparable with mGluR5 and mGluR2/3. Analgesic effects of FTIDC were seen in the formalin test but not in the tail immersion test. FTIDC selectively blocked methamphetamine-induced hyperlocomotion and disruption of prepulse inhibition, whereas MPEP and LY379268 did not alter those behaviors, suggesting that pharmacological blockade of mGluR1 could result in antipsychotic-like effects. FTIDC did not elicit catalepsy or impair motor functions at 10 times higher dose than doses showing antipsychotic-like action. In conclusion, blockade of mGluR1 showed antipsychotic-like effects without impairing motor functions, whereas blockade of mGluR5 and activation of mGluR2/3 did not display such activities.
Satow
Akio
A
Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd., 3 Okubo, Tsukuba, Ibaraki 300-2611, Japan. akio_sato@merck.com
Maehara
Shunsuke
S
Ise
Satoko
S
Hikichi
Hirohiko
H
Fukushima
Miyuki
M
Suzuki
Gentaroh
G
Kimura
Toshifumi
T
Tanak
Takeshi
T
Ito
Satoru
S
Kawamoto
Hiroshi
H
Ohta
Hisashi
H
D000494:Allosteric Regulation; D000818:Animals; D014151:Anti-Anxiety Agents / Q000737:chemistry / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D005334:Fever / Q000188:drug therapy; D008297:Male; D018782:Maze Learning; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D010146:Pain / Q000188:drug therapy; D051381:Rats; D017207:Rats, Sprague-Dawley; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists* / Q000037:antagonists & inhibitors*; D013216:Reflex, Startle / Q000187:drug effects; D014230:Triazoles / Q000737:chemistry / Q000494:pharmacology*; D014828:Vocalization, Animal / Q000187:drug effects
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; D014151:Anti-Anxiety Agents; C578936:Grm5 protein, mouse; C578937:Grm5 protein, rat; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D014230:Triazoles; C108822:metabotropic glutamate receptor 2; C102718:metabotropic glutamate receptor 3; C104077:metabotropic glutamate receptor type 1