Pharmacological probes for elucidating the physiological role of glutamate receptors

用于阐明谷氨酸受体生理作用的药理学探针

• 批准号: 07672433
• 负责人: SHINOZAKI Haruhiko
• 金额: $ 1.6万
• 依托单位: The Tokyo Metropolitan Institute of Medical Science
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1995
• 资助国家: 日本
• 起止时间: 1995 至 1996
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-07672433/
• 关键词: Long term depression; synaptic transmission; neural plasticity; priming; metabotropic glutamate receptor; glutamate transporter; glutamate; piming; シナブス伝達; 長期抑圧; 2-(carboxycyclopropyl)glycine; 立体配座; フッ素置換体; 神経細胞死; NMDA型受容体

Pharmacological activities of 8 stereoisomers of 2- (2-carboxy-3,3-difluorocyclopropyl) glycine (3', 3'-difluoro-CCGs) were determined. All 3', 3'-difluoro-CCGs caused depolarization of motoneurons of newborn rats with a large variety of depolarizing activities. (2S,2'S,2'S) -and (2S,2'R,2'S) -2- (2-carboxy-3,3-difluorocyclopropyl) glycine (L-F_2CCG-I and L-F_2CCG-IV,respectively) were the most potent on a molar basis in causing depolarization among them, their threshold concentrations being about 1muM.The depolarization evoked by L-F_2CCG-I (10-30muM) was effectively depressed by MCPG (1mM), and was only slightly decreased by high concentrations of D-AP5 (100muM), but not by CNQX (100muM), suggesting that L-F_2CCG-I activates metabotropic glutamate receptors. L-F_2CCG-I preferentially depressed the monosynaptic component of the spinal reflex about 3 times as much as more effectively than (2S,1'S,2'S) -2- (carboxy-cyclopropyl) glycine (L-CCG-I). The inhibitory action of L-F_2CCG-I (0.2 … More muM-0.7muM) on monosynaptic excitation was effectively blocked by MCCG (0.3mM-1mM) and MAP4 (0.3mM). DL-alpha-Aminopimelic acid, at concentrations lower than 0.1mM (the threshold concentration : 3muM), selectively potentiated the inhibition of monosynaptic excitation caused by L-CCG-I,L-F_2CCG-I and (2S,1'S,2'R,3'S) -2- (2-carboxy-3-methoxymethylcyclopropyl) glycine (trans-MCG-I), but the action of (2S,1'R,2'R,3'R) -2- (2,3-dicarboxycyclopropyl) glycine (DCG-IV), L-AP4, (1S,3R) -ACPD and baclofen was not affected at all by LD-alpha-aminopimelic acid. Once L-F_2CCG-I was applied to the spinal cord preparation of newborn rats, very low concentrations of L-glutamate (for example, 30muM), DL-alpha-aminopimelic acid and carbocysteine (3-100muM), which did not show any detectable pharmacological actions, got an activity to decrease the amplitude of the monosynaptic component of spinal reflexes, showing the 'L-F_2CCG-I priming'. L-F_2CCG-I,DL-alpha-aminopimelic acid and carbocysteine would provide useful pharmacological probes for elucidating the mechanisms underlying the priming action of mGluR agonists. Less

测定了 2-（2-羧基-3,3-二氟环丙基）甘氨酸（3',3'-二氟-CCG）的 8 种立体异构体的药理活性。所有 3', 3'-二氟-CCG 都会引起新生大鼠运动神经元的去极化，并具有多种去极化活性。 (2S,2'S,2'S) - 和 (2S,2'R,2'S) -2- (2-羧基-3,3-二氟环丙基) 甘氨酸（分别为 L-F_2CCG-I 和 L-F_2CCG-IV）在它们当中引起去极化的能力最强，其阈浓度约为 1μM。 L-F_2CCG-I (10-30μM) 被 MCPG (1mM) 有效抑制，并且仅被高浓度的 D-AP5 (100μM) 轻微降低，但不被 CNQX (100μM) 降低，表明 L-F_2CCG-I 激活代谢型谷氨酸受体。 L-F_2CCG-I优先抑制脊髓反射的单突触成分，其效果比(2S,1'S,2'S)-2-(羧基-环丙基)甘氨酸(L-CCG-I)有效约3倍。 L-F_2CCG-I (0.2 … 更多 muM-0.7muM) 对单突触兴奋的抑制作用被 MCCG (0.3mM-1mM) 和 MAP4 (0.3mM) 有效阻断。 DL-α-Aminopimelic Acid，浓度低于0.1mM（阈值浓度：3μM），选择性增强对L-CCG-I、L-F_2CCG-I和(2S,1'S,2'R,3'S)-2-(2-carboxy-3-methoxymethylcycloloid)glycine引起的单突触兴奋的抑制 (反式-MCG-I)，但(2S,1'R,2'R,3'R)-2-(2,3-二羧基环丙基)甘氨酸(DCG-IV)、L-AP4、(1S,3R)-ACPD和巴氯芬的作用完全不受LD-α-氨基庚二酸影响。将L-F_2CCG-I应用于新生大鼠的脊髓标本后，极低浓度的L-谷氨酸（例如30μM）、DL-α-氨基庚二酸和羧甲司坦（3-100μM）没有表现出任何可检测到的药理作用，却具有降低脊髓反射单突触成分振幅的活性，显示出 “L-F_2CCG-I 启动”。 L-F_2CCG-I、DL-α-氨基庚二酸和羧甲司坦将为阐明 mGluR 激动剂引发作用的机制提供有用的药理学探针。较少的

项目成果

Poncer,J-C.: "Dual modulation of synaptic inhibition by distinct metabotropic glutamate receptors in the rat hippocampus." J.Physiol.485. 121-134 (1995)

Poncer，J-C.：“大鼠海马中不同代谢型谷氨酸受体对突触抑制的双重调节。”

篠崎温彦: "興奮性アミノ酸と神経細胞死." 脳と発達. 27. 104-112 (1995)

Atsuhiko Shinozaki：“兴奋性氨基酸和神经元死亡。” 27. 104-112 (1995)。

Shinozaki,H.: "Amiotrophic Lateral Sclerosis : Progress and Perspectives in Basic Research and Clinical Application" Watanabe,Y.,Farnsworth,N.R.and Shibuya,K.(印刷中),

Shinozaki, H.：“肌萎缩侧索硬化症：基础研究和临床应用的进展和展望”Watanabe, Y.、Farnsworth, N.R. 和 Shibuya, K.（出版中），

Kwak, S.: Protection of acromelic acid-induced neuronal death in the rat spinal cord by an mGluR agonist.In : Amiotrophic Lateral Sclerosis : Progress and Perspectivesin Basic Research and Clinical Application. eds. Nakao, I., and Hirano, A., 265 (1996)

Kwak, S.：通过 mGluR 激动剂保护大鼠脊髓中肢端酸诱导的神经元死亡。In：肌萎缩性脊髓侧索硬化症：基础研究和临床应用的进展和前景。

Miyamoto,M.: "Anticonvulsive and neuroprotective actions of a potent agonist(DCG-IV)for class II metabotropic glutamate receptors against intraventricular kainate in the rat." Neurosci.77. 131-140 (1997)

Miyamoto,M.：“II 类代谢型谷氨酸受体的强效激动剂 (DCG-IV) 对大鼠心室内红藻氨酸的抗惊厥和神经保护作用。”