三环吲哚 -2- 羧酸：对 N-甲基-D-天冬氨酸受体甘氨酸结合位点具有高度体内活性和选择性的拮抗剂。

Tricyclic indole-2-carboxylic acids: highly in vivo active and selective antagonists for the glycine binding site of the NMDA receptor.

作者信息

Katayama Seiji, Ae Nobuyuki, Kodo Toru, Masumoto Shuji, Hourai Shinji, Tamamura Chika, Tanaka Hiroyasu, Nagata Ryu

机构信息

Research Division, Sumitomo Pharmaceuticals Co., Ltd, 1-98 Kasugadenaka 3-chome, Konohana-ku, Osaka 554-0022, Japan.

出版信息

J Med Chem. 2003 Feb 27;46(5):691-701. doi: 10.1021/jm020239l.

DOI:10.1021/jm020239l

PMID:12593650

Abstract

A series of tricyclic indole-2-carboxylic acid derivatives were synthesized and evaluated by the radioligand binding assay and the anticonvulsant effects in the mouse NMDA-induced seizure model. Among them, derivatives of 3S-(-)-4 such as 3a, 3f, and 3g which had certain zwitterionic anilides showed high affinity to the NMDA-glycine binding site. The absolute configuration of 3S-(-)-4 was confirmed by X-ray crystallographic analysis. In particular, 3g (SM-31900) was found to be a highly active glycine antagonist for both in vitro and in vivo assays (K(i) = 1.0 +/- 0.1 nM, ED(50) = 2.3 mg/kg, iv) and also showed high selectivity for the glycine site. In addition, 3g was soluble enough in aqueous media (>10 mg/mL at pH 7.4) to use for medications by intravenous injection.

摘要

合成了一系列三环吲哚 -2- 羧酸衍生物，并通过放射性配体结合试验和小鼠 NMDA 诱导的癫痫模型中的抗惊厥作用进行评估。其中，具有一定两性离子苯胺类的 3S-(-)-4 的衍生物，如 3a、3f 和 3g，对 NMDA - 甘氨酸结合位点表现出高亲和力。通过 X 射线晶体学分析确定了 3S-(-)-4 的绝对构型。特别地，发现 3g（SM - 31900）在体外和体内试验中都是一种高活性的甘氨酸拮抗剂（K(i) = 1.0 +/- 0.1 nM，ED(50) = 2.3 mg/kg，静脉注射），并且对甘氨酸位点也表现出高选择性。此外，3g 在水性介质中具有足够的溶解性（在 pH 7.4 时>10 mg/mL），可用于静脉注射给药。