Satow Akio, Maehara Shunsuke, Ise Satoko, Hikichi Hirohiko, Fukushima Miyuki, Suzuki Gentaroh, Kimura Toshifumi, Tanak Takeshi, Ito Satoru, Kawamoto Hiroshi, Ohta Hisashi
Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd., 3 Okubo, Tsukuba, Ibaraki 300-2611, Japan.
J Pharmacol Exp Ther. 2008 Aug;326(2):577-86. doi: 10.1124/jpet.108.138107. Epub 2008 May 16.
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.
使用一种强效且选择性的代谢型谷氨酸受体(mGluR)1变构拮抗剂FTIDC [4-[1-(2-氟吡啶-3-基)-5-甲基-1H-1,2,3-三唑-4-基]-N-异丙基-N-甲基-3,6-二氢吡啶-1(2H)-甲酰胺],并与mGluR5变构拮抗剂以及mGluR2/3正构激动剂进行比较,研究了mGluR1在整合脑功能中的作用。FTIDC可减少母婴分离诱导的超声发声和应激诱导的体温过高,而不影响高架十字迷宫中的行为。mGluR5拮抗剂2-甲基-6-(苯乙炔基)-吡啶(MPEP)和mGluR2/3激动剂LY379268 [(1R,4R,5S,6R)-4-氨基-2-氧杂双环[3.1.0]己烷-4,6-二羧酸]在这些模型中显示出抗焦虑活性,表明突触后mGluR1参与了与mGluR5和mGluR2/3相当的应激相关反应。在福尔马林试验中观察到FTIDC的镇痛作用,但在尾浸试验中未观察到。FTIDC选择性地阻断了甲基苯丙胺诱导的运动亢进和前脉冲抑制的破坏,而MPEP和LY379268并未改变这些行为,表明mGluR1的药理学阻断可能导致类似抗精神病的作用。在比显示类似抗精神病作用的剂量高10倍的剂量下,FTIDC未引发僵住症或损害运动功能。总之,mGluR1的阻断显示出类似抗精神病的作用而不损害运动功能,而mGluR5的阻断和mGluR2/3的激活并未表现出此类活性。
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