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

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

doi:10.1021/jm020239l

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

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

Authors

Seiji Katayama¹, Nobuyuki Ae, Toru Kodo, Shuji Masumoto, Shinji Hourai, Chika Tamamura, Hiroyasu Tanaka, Ryu Nagata

Affiliation

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

PMID: 12593650
DOI: 10.1021/jm020239l

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.

MeSH terms

Animals
Anticonvulsants / chemical synthesis*
Anticonvulsants / pharmacokinetics
Anticonvulsants / pharmacology
Binding Sites
Binding, Competitive
Brain / drug effects
Brain / metabolism
Brain / pathology
Brain Infarction / drug therapy
Brain Infarction / etiology
Brain Infarction / pathology
Crystallography, X-Ray
Glycine / metabolism*
Heterocyclic Compounds, 3-Ring / chemical synthesis*
Heterocyclic Compounds, 3-Ring / chemistry
Heterocyclic Compounds, 3-Ring / pharmacology
Indoles / chemical synthesis*
Indoles / chemistry
Indoles / pharmacokinetics
Indoles / pharmacology
Infarction, Middle Cerebral Artery / complications
Infarction, Middle Cerebral Artery / drug therapy
Infarction, Middle Cerebral Artery / pathology
Mice
Models, Molecular
Neuroprotective Agents / chemical synthesis*
Neuroprotective Agents / pharmacokinetics
Neuroprotective Agents / pharmacology
Radioligand Assay
Rats
Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors
Receptors, N-Methyl-D-Aspartate / metabolism*
Seizures / drug therapy
Solubility
Stereoisomerism
Structure-Activity Relationship

Substances

Anticonvulsants
Heterocyclic Compounds, 3-Ring
Indoles
Neuroprotective Agents
Receptors, N-Methyl-D-Aspartate
SM 31900
Glycine