mdl-104653 and Seizures

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.

Topics: Animals; Binding, Competitive; Blood-Brain Barrier; Cell Line; Cytoprotection; Electroshock; Glycine; Humans; In Vitro Techniques; Male; Mice; Protein Subunits; Pyridones; Quantitative Structure-Activity Relationship; Radioligand Assay; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Recombinant Proteins; Seizures; Thiophenes; Transfection

MDL 104,653 (3-phenyl-4-hydroxy-7-chloro-quinolin-2(1H)-one), acts as an antagonist at the glycine site of the NMDA receptor. MDL 104,653 protects against sound-induced clonic seizures in DBA/2 mice following intracerebroventricular (ED50 = 19.1 nmol, 30 min), intraperitoneal (i.p.; ED50 = 6.1 mumol/kg, 45 min), or oral (ED50 = 23.0 mumol/kg, 2 h) administration. Optimal protection by MDL 104,653 was observed 15-60 min after i.p. administration, and the therapeutic index, as assessed by rotarod performance, was 4.0 at 45 min after i.p. administration. Fully amygdala-kindled motor seizures in rats were significantly reduced at 15, 30 and 60 min, and the duration of the after-discharge was significantly shortened at 30 min after the i.p. administration of 74 mumol/kg MDL 104,653. A lower dose of MDL 104,653 (37 mumol/kg) had no significant effect on either motor seizures or after-discharge duration. The rate of amygdala kindling was also significantly retarded following the daily administration of 56 mumol/kg MDL 104,653 (1 times daily for 6 days; i.p. 30 min before kindling stimulus).

Topics: Administration, Oral; Amygdala; Analysis of Variance; Animals; Behavior, Animal; Dose-Response Relationship, Drug; Female; Injections, Intraperitoneal; Injections, Intraventricular; Kindling, Neurologic; Male; Mice; Mice, Inbred DBA; Quinolones; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Seizures; Sound