Design and development of agonists for metabotropic glutamate receptors to protect against neuronal death

测定了2-（2-羧基-3，3-二氟环丙基）甘氨酸（3 '，3'-difluoro-CCGs）的8个立体异构体的药理活性。所有3 '，3'-二氟-CCGs均引起新生大鼠运动神经元的去极化，其去极化活动具有多种多样性。(2S，1'S，2'S）-和（2S，1'R，2'S）-2-（2-羧基-3，3-二氟环丙基）甘氨酸L-F_2CCG-I和L-F_2CCG-IV的去极化作用最强，其阈值浓度约为1 μ M（10- 30 μ M）可被MCPG（1 mM）有效地抑制，而仅被高浓度的D-AP 5（100 μ M）轻微地降低，但不被CNQX（100 μ M）所抑制，这表明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，其抑制作用是（2S，1 ′ S，2 ′ S）-2-（羧基-环丙基）甘氨酸（L-CCG-I）的3倍。L-F_2CCG-I（0. ...更多信息 MCCG（0.3mM-1 mM）和MAP 4（0.3mM）能有效地阻断MCCG（0.2 μ M-0.7 μ M）对单突触兴奋的作用。DL-α-氨基庚二酸，浓度低于0.1 mM（阈值浓度：3 μ M），选择性地增强L-CCG-I、L-F_2CCG-I和L-F_2CCG-I对单突触兴奋的抑制作用，（2S，1'S，2'R，3'S）-2-（2-羧基-3-甲氧基甲基环丙基）甘氨酸DL-α-氨基庚二酸对（2S，1 'R，2' R，3 'R）-2-（2，3-二羧基环丙基）甘氨酸（DCG-IV）、L-AP 4、（1 S，3R）-ACPD和巴氯芬的作用没有影响。将L-F_2CCG-I作用于新生大鼠脊髓标本，极低浓度的L-谷氨酸（如30 μ M）、DL-α-氨基庚二酸（DL-α-aminopimelic acid）和羧半胱氨酸（carbocysteine）（3- 100 μ M）（未显示任何可检测的药理作用）均产生降低脊髓反射单突触成分振幅的活性，表现为“L-F_2CCG-I启动”。L-F_2CCG-I、DL-α-氨基庚二酸和羧半胱氨酸为阐明mGluR激动剂的启动作用机制提供了有用的药理学探针。少

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,1'S,2'S) -and (2S,1'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 1 muM.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. … More 2muM-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-MDG-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 DL-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