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.
Subject(s)
Cytoprotection , Glycine/metabolism , Pyridones/chemical synthesis , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Thiophenes/chemistry , Animals , Binding, Competitive , Blood-Brain Barrier/metabolism , Cell Line , Electroshock , Glycine/toxicity , Humans , In Vitro Techniques , Male , Mice , Protein Subunits/antagonists & inhibitors , Protein Subunits/genetics , Protein Subunits/metabolism , Pyridones/chemistry , Pyridones/pharmacology , Quantitative Structure-Activity Relationship , Radioligand Assay , Rats , Rats, Wistar , Receptors, N-Methyl-D-Aspartate/genetics , Receptors, N-Methyl-D-Aspartate/metabolism , Recombinant Proteins/antagonists & inhibitors , Recombinant Proteins/genetics , Recombinant Proteins/metabolism , Seizures/etiology , Seizures/prevention & control , TransfectionABSTRACT
A series of 2-alkyl-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indoles were synthesized and evaluated for their 5-HT6 activity. The most potent agonist in this series was 5-chloro-2-methyl-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole with an IC50=7.4 nM in 3H-LSD binding and an EC50=1.0 nM in a functional assay measuring production of cyclic AMP.
