Pharmacological probes for elucidating the physiological role of glutamate receptors

测定了8种2-（2-羧基-3,3-二氟环丙基）甘氨酸立体异构体（3′，3′-二氟- ccgs）的药理活性。所有的3',3'-二氟- ccgs都能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, 2S, 2S）和(2S,2'R, 2S) -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）在摩尔基础上对它们的去极化作用最强，它们的阈值浓度约为1muM。MCPG （1mM）可有效抑制L-F_2CCG-I （10-30muM）引起的去极化，高浓度D-AP5 （100muM）仅能轻微降低去极化，而CNQX （100muM）则不能，说明L-F_2CCG-I激活了代谢性谷氨酸受体。L-F_2CCG-I对脊髓反射单突触组分的优先抑制作用是(2S, 1s, 2S) -2-（羧基环丙基）甘氨酸（L-CCG-I）的3倍。mcg （0.3mM- 1mm）和MAP4 （0.3mM）可有效阻断L-F_2CCG-I（0.2…More muM-0.7muM）对单突触兴奋的抑制作用。dl - α -氨基苯甲酸在浓度低于0.1mM（阈值浓度为3muM）时，选择性地增强了L-CCG-I、L-F_2CCG-I和(2S,1'S,2' r,3'S) -2-（2-羧基-3-甲氧基甲基环丙基）甘氨酸（反式mcg - i）对单突触兴奋的抑制作用，而(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 -氨基苯甲酸的影响。将L-F_2CCG-I应用于新生大鼠脊髓制备后，极低浓度的l -谷氨酸（如30muM）、dl - α -氨基苯甲酸和碳半胱氨酸（3-100muM）在未表现出任何药理作用的情况下，具有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 -氨基苯甲酸和碳半胱氨酸将为阐明mGluR激动剂启动作用的机制提供有用的药理学探针。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,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