title: Novel indole-2-carboxylates as ligands for the strychnine-insensitive N-methyl-D-aspartate-linked glycine receptor.
abstract: A series of indole-2-carboxylates were prepared and evaluated for their ability to inhibit the binding at the strychnine-insensitive glycine receptor that is associated with the NMDA-PCP-glycine receptor complex. All of the compounds were selective for the glycine site relative to other sites on the receptor macrocomplex and several of the compounds in this series were found to have submicromolar affinity for this receptor. The lead compound, 2-carboxy-6-chloro-3-indoleacetic acid (Ki = 1.6 microM vs [3H]glycine), was also found to noncompetitively inhibit the binding of MK-801, a ligand for the phencyclidine site on the receptor macrocomplex. These latter data suggest that the compound functions as an antagonist at the strychnine-insensitive glycine receptor. The structural activity relationships within this series of indole-2-carboxylates is discussed and several key pharmacophores are identified for this series of glycine ligands. In general, the most potent compounds were the C-3 acetamides, with N-propyl-2-carboxy-6-chloro-3-indoleacetamide having the highest receptor affinity.
authors.affiliation: Central Nervous System Diseases Research, G.D. Searle & Company, St. Louis, Missouri 63198.
authors.forename: N M
authors.initials: NM
authors.lastname: Gray
authors.forename: M S
authors.initials: MS
authors.lastname: Dappen
authors.forename: B K
authors.initials: BK
authors.lastname: Cheng
authors.forename: A A
authors.initials: AA
authors.lastname: Cordi
authors.forename: J P
authors.initials: JP
authors.lastname: Biesterfeldt
authors.forename: W F
authors.initials: WF
authors.lastname: Hood
authors.forename: J B
authors.initials: JB
authors.lastname: Monahan
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D002264:Carboxylic Acids / Q000138:chemical synthesis* / Q000494:pharmacology; D005998:Glycine / Q000378:metabolism; D007202:Indicators and Reagents; D007211:Indoles / Q000138:chemical synthesis* / Q000494:pharmacology; D008024:Ligands; D008297:Male; D015394:Molecular Structure; D010622:Phencyclidine / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D011919:Rats, Inbred Strains; D018009:Receptors, Glycine; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000378:metabolism*; D017981:Receptors, Neurotransmitter / Q000187:drug effects / Q000378:metabolism*; D017478:Receptors, Phencyclidine; D013329:Structure-Activity Relationship; D013331:Strychnine / Q000494:pharmacology
chemical_list: D002264:Carboxylic Acids; D007202:Indicators and Reagents; D007211:Indoles; D008024:Ligands; D018009:Receptors, Glycine; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter; D017478:Receptors, Phencyclidine; D013331:Strychnine; D010622:Phencyclidine; D005998:Glycine