| Co-Investigator(Kenkyū-buntansha) |
KONISHI Shiro Mitsubish Kasei Institute of Life-Science, Researcher, 研究員
MIYAMOTO Masashi Kirin Brewery Co. Ltd., Pharmaceutical Research Laboratory, Researcher, 医薬探索研究所, 研究員
IZAWA Toshio Kirin Brewery Co. Ltd., Pharmaceutical Research Laboratory, Researcher, 医薬探索研究所, 研究員
UYAMA Yoshiaki The Tokyo Metropolitan Institute of Medical Science, Pharmacology, Researcher., 薬理研究部門, 研究員 (20281686)
ISHIDA Michiko The Tokyo Metropolitan Institute of Medical Science, Pharmacology, Researcher., 薬理研究部門, 研究員 (90124437)
小西 史朗 (株)三菱化学生命科学研究所, 研究員
伊沢 敏雄 (株)キリンビール, 医薬探索研究所, 研究員
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| Research Abstract |
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.
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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
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