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与代谢型谷氨酸受体5拮抗剂和代谢型谷氨酸受体2/3激动剂相比,代谢型谷氨酸受体1拮抗剂在啮齿动物中的药理作用:使用选择性变构代谢型谷氨酸受体1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]的详细研究

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].

作者信息

Satow Akio, Maehara Shunsuke, Ise Satoko, Hikichi Hirohiko, Fukushima Miyuki, Suzuki Gentaroh, Kimura Toshifumi, Tanak Takeshi, Ito Satoru, Kawamoto Hiroshi, Ohta Hisashi

机构信息

Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd., 3 Okubo, Tsukuba, Ibaraki 300-2611, Japan.

出版信息

J Pharmacol Exp Ther. 2008 Aug;326(2):577-86. doi: 10.1124/jpet.108.138107. Epub 2008 May 16.


DOI:10.1124/jpet.108.138107
PMID:18487514
Abstract

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.

摘要

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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