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J Med Chem ; 46(5): 691-701, 2003 Feb 27.
Article in English | MEDLINE | ID: mdl-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.


Subject(s)
Anticonvulsants/chemical synthesis , Glycine/metabolism , Heterocyclic Compounds, 3-Ring/chemical synthesis , Indoles/chemical synthesis , Neuroprotective Agents/chemical synthesis , Receptors, N-Methyl-D-Aspartate/metabolism , Animals , 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 , Heterocyclic Compounds, 3-Ring/chemistry , Heterocyclic Compounds, 3-Ring/pharmacology , 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/pharmacokinetics , Neuroprotective Agents/pharmacology , Radioligand Assay , Rats , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Seizures/drug therapy , Solubility , Stereoisomerism , Structure-Activity Relationship
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