title: Synthesis of thieno[2,3-b]pyridinones acting as cytoprotectants and as inhibitors of [3H]glycine binding to the N-methyl-D-aspartate (NMDA) receptor.
abstract: The standard glycine site antagonist of the N-methyl-D-aspartate (NMDA) receptor, 3-phenyl-4-hydroxyquinolin-2(1H)-one (21), was used as a template for bioisostere benzene/thiophene exchange. Phenylacetylation of aminothiophene carboxylic acid methyl esters and subsequent cyclization delivered the three possible thienopyridinone isomers. 4-Hydroxy-5-phenylthieno[2,3-b]pyridin-6(7H)-one (3a), with the shortest distance between the sulfur and the nitrogen atom, was the most potent isomer (K(i) against the binding of [(3)H]glycine to rat membranes 16 microM), comparable in potency to the model quinolinone (21, 12 microM). Replacement of the phenyl substituent of 21 by a 2-thienyl residue resulted in a 2-5-fold loss in potency and was abandoned. In the thieno part of the thienopyridinone nucleus, the most successful substituents were halogen (Cl or Br) close to the sulfur atom and short alkyl chains at the other position, resulting in 7h, 8h, 8i, and 8m, with K(i) values between 5.8 and 10.5 nM. Introduction of a 3'-phenoxy moiety yielded several compounds with still higher potencies (18h, 18i, 18l, and 18m; K(i) between 1.1 and 2.0 nM). Quantitative structure-activity relationship (QSAR) calculations resulted in a consistent interpretation of the potencies of most compounds. Several of these 3'-phenoxy derivatives protected mouse fibroblast cell lines with transfected NMDA receptors from glutamate-induced toxicity. In addition, we report in vivo results for four of these compounds.
authors.affiliation: Institute of Pharmaceutical Chemistry, Johann Wolfgang Goethe University, D-60439 Frankfurt/Main, Germany.
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Buchstaller
authors.forename: Carsten D
authors.initials: CD
authors.lastname: Siebert
authors.forename: Ralf
authors.initials: R
authors.lastname: Steinmetz
authors.forename: Ina
authors.initials: I
authors.lastname: Frank
authors.forename: Michael L
authors.initials: ML
authors.lastname: Berger
authors.forename: Rudolf
authors.initials: R
authors.lastname: Gottschlich
authors.forename: Joachim
authors.initials: J
authors.lastname: Leibrock
authors.forename: Michael
authors.initials: M
authors.lastname: Krug
authors.forename: Dieter
authors.initials: D
authors.lastname: Steinhilber
authors.forename: Christian R
authors.initials: CR
authors.lastname: Noe
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D001812:Blood-Brain Barrier / Q000378:metabolism; D002460:Cell Line; D019610:Cytoprotection; D004597:Electroshock; D005998:Glycine / Q000378:metabolism* / Q000633:toxicity; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D021122:Protein Subunits / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011728:Pyridones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D012640:Seizures / Q000209:etiology / Q000517:prevention & control; D013876:Thiophenes / Q000737:chemistry*; D014162:Transfection
chemical_list: C120997:NR2A NMDA receptor; D021122:Protein Subunits; D011728:Pyridones; D016194:Receptors, N-Methyl-D-Aspartate; D011994:Recombinant Proteins; D013876:Thiophenes; D005998:Glycine