Chiarugi A, Carpenedo R, Molina M T, Mattoli L, Pellicciari R, Moroni F
Department of Preclinical and Clinical Pharmacology, University of Florence, Italy.
J Neurochem. 1995 Sep;65(3):1176-83. doi: 10.1046/j.1471-4159.1995.65031176.x.
Several kynurenine analogues were synthesized and tested as inhibitors of the enzymes kynurenine hydroxylase and/or kynureninase with the aim of identifying new compounds able to inhibit the synthesis of quinolinic acid (an endogenous excitotoxin) and to increase that of kynurenic acid, an endogenous antagonist of ionotropic glutamate receptors. Among these analogues, we selected m-nitrobenzoylalanine (mNBA) as an inhibitor of kynurenine hydroxylase and o-methoxybenzoylalanine (oMBA) as an inhibitor of kynureninase. When administered to rats, mNBA was more potent than oMBA in increasing the content of kynurenine and of kynurenic acid in the brain, blood, liver, and kidney. This confirms that hydroxylation is the main pathway of kynurenine metabolism. Both mNBA and oMBA (50-400 mg/kg i.p.) increased the concentration of kynurenate in hippocampal extracellular spaces (as measured with a microdialysis technique) and, when simultaneously injected, their effects were additive. This biochemical effect was associated with a decrease in locomotor activity in rats and with a protection of audiogenic convulsions in DBA/2 mice. In conclusion, the results of the present experiments indicate the possibility of increasing the neosynthesis of kynurenic acid by inhibiting the enzymes that metabolize kynurenine to 3-hydroxykynurenine or to anthranilic acid. The increased synthesis of kynurenate is associated with behavioral effects such as sedation and protection from seizures, which suggests a functional antagonism of the excitatory amino acid receptors.
合成了几种犬尿氨酸类似物，并作为犬尿氨酸羟化酶和/或犬尿氨酸酶的抑制剂进行测试，目的是鉴定能够抑制喹啉酸（一种内源性兴奋性毒素）合成并增加犬尿酸（离子型谷氨酸受体的内源性拮抗剂）合成的新化合物。在这些类似物中，我们选择间硝基苯甲酰丙氨酸（mNBA）作为犬尿氨酸羟化酶的抑制剂，邻甲氧基苯甲酰丙氨酸（oMBA）作为犬尿氨酸酶的抑制剂。给大鼠给药时，mNBA在增加大脑、血液、肝脏和肾脏中犬尿氨酸和犬尿酸含量方面比oMBA更有效。这证实了羟基化是犬尿氨酸代谢的主要途径。mNBA和oMBA（腹腔注射50 - 400 mg/kg）均增加了海马细胞外间隙中犬尿酸盐的浓度（用微透析技术测量），并且当同时注射时，它们的作用是相加的。这种生化效应与大鼠运动活动的减少以及对DBA/2小鼠听源性惊厥的保护作用相关。总之，本实验结果表明，通过抑制将犬尿氨酸代谢为3 - 羟基犬尿氨酸或邻氨基苯甲酸的酶来增加犬尿酸新合成具有可能性。犬尿酸盐合成的增加与诸如镇静和抗惊厥等行为效应相关，这表明对兴奋性氨基酸受体存在功能性拮抗作用。
