Pellicciari R, Natalini B, Costantino G, Mahmoud M R, Mattoli L, Sadeghpour B M, Moroni F, Chiarugi A, Carpenedo R
Istituto di Chimica Farmaceutica e Tecnica Farmaceutica, Università di Perugia, Italy.
J Med Chem. 1994 Mar 4;37(5):647-55. doi: 10.1021/jm00031a015.
The synthesis of (o-nitrobenzoyl)-, (m-nitrobenzoyl)-, and (p-nitrobenzoyl)alanine (o-, m-, and p-NBA), three new kynurenine analogues, and their evaluation as inhibitors of kynureninase and kynurenine-3-hydroxylase are reported. The most potent of these compounds, m-NBA, has an IC50 of 0.9 +/- 0.1 microM as an inhibitor of kynurenine-3-hydroxylase and of 100 +/- 12 microM as an inhibitor of kynureninase. When administered to rats, m-NBA significantly increases the concentration of kynurenine and kynurenic acid in the brain as well as in blood and in the liver. m-NBA has also been shown to increase the concentration of kynurenic acid in hippocampal extracellular fluid. This increase is associated with sedative and anticonvulsant activities, thus confirming the possibility of antagonizing L-glutamate-mediated effects by modulating the kynurenine pathway of L-tryptophan metabolism.
报道了三种新的犬尿氨酸类似物（邻硝基苯甲酰基丙氨酸、间硝基苯甲酰基丙氨酸和对硝基苯甲酰基丙氨酸，即o-、m-和p-NBA）的合成及其作为犬尿氨酸酶和犬尿氨酸-3-羟化酶抑制剂的评估。这些化合物中最有效的m-NBA，作为犬尿氨酸-3-羟化酶抑制剂的IC50为0.9±0.1微摩尔，作为犬尿氨酸酶抑制剂的IC50为100±12微摩尔。给大鼠给药时，m-NBA显著增加大脑以及血液和肝脏中犬尿氨酸和犬尿酸的浓度。m-NBA还被证明可增加海马细胞外液中犬尿酸的浓度。这种增加与镇静和抗惊厥活性相关，从而证实了通过调节L-色氨酸代谢的犬尿氨酸途径拮抗L-谷氨酸介导的作用的可能性。
