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

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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