title: Tricyclic indole-2-carboxylic acids: highly in vivo active and selective antagonists for the glycine binding site of the NMDA receptor.
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.
authors.affiliation: Research Division, Sumitomo Pharmaceuticals Co., Ltd, 1-98 Kasugadenaka 3-chome, Konohana-ku, Osaka 554-0022, Japan.
authors.forename: Seiji
authors.initials: S
authors.lastname: Katayama
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Ae
authors.forename: Toru
authors.initials: T
authors.lastname: Kodo
authors.forename: Shuji
authors.initials: S
authors.lastname: Masumoto
authors.forename: Shinji
authors.initials: S
authors.lastname: Hourai
authors.forename: Chika
authors.initials: C
authors.lastname: Tamamura
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Tanaka
authors.forename: Ryu
authors.initials: R
authors.lastname: Nagata
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001665:Binding Sites; D001667:Binding, Competitive; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D020520:Brain Infarction / Q000188:drug therapy / Q000209:etiology / Q000473:pathology; D018360:Crystallography, X-Ray; D005998:Glycine / Q000378:metabolism*; D006575:Heterocyclic Compounds, 3-Ring / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D020244:Infarction, Middle Cerebral Artery / Q000150:complications / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D008958:Models, Molecular; D018696:Neuroprotective Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012640:Seizures / Q000188:drug therapy; D012995:Solubility; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000927:Anticonvulsants; D006575:Heterocyclic Compounds, 3-Ring; D007211:Indoles; D018696:Neuroprotective Agents; D016194:Receptors, N-Methyl-D-Aspartate; C466317:SM 31900; D005998:Glycine