Vol. 283, Issue 3, 1264-1275, 1997

Novel Systemically Active Antagonists of the Glycine Site of the N-Methyl-D-aspartate Receptor: Electrophysiological, Biochemical and Behavioral Characterization

Chris G. Parsons, Wojciech Danysz, Günter Quack, Sabine Hartmann, Bianke Lorenz, Christine Wollenburg, Leokadia Baran, Edmund Przegalinski, Wojciech Kostowski, Pawel Krzascik, Boris Chizh and P. Max. Headley

Department of Pharmacology, Merz and Co., D-60318 Frankfurt am Main, Germany (C.G.P., W.D., G.Q., S.H., B.L., C.W.), Institute of Pharmacology PAN, Smetna 12, Cracow, Poland (L.B., E.P.), Department of Pharmacology, Institute of Psychiatry and Neurology, Sobieskiego 1-9, Warsaw, Poland (W.K., P.K.) and Department of Physiology, School of Medical Sciences, University Walk, Bristol BS8 1TD, England (B.C., P.M.H.)

A series of novel tricyclic pyrido-phthalazine-dione derivatives was tested for antagonistic effects at the strychnine-insensitive modulatory site of the N-methyl-D-aspartate (NMDA) receptor (glycine_B). All compounds displaced [³H]MDL-105,519 binding to rat cortical membranes with IC₅₀ values of between 90 nM and 3.6 µM. In patch-clamp experiments, steady-state inward current responses of cultured hippocampal neurons to NMDA (200 µM, glycine 1 µM) were antagonized by these same compounds with IC₅₀ values of 0.14 to 13.8 µM. The antagonism observed was typical for glycine_B antagonists, i.e., they induced desensitization and their effects were not use or voltage dependent. Moreover, increasing concentrations of glycine were able to decrease their apparent potency. Much higher concentrations (>100 µM) were required to antagonize -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-induced currents. They were potent, systemically active NMDA receptor antagonists in vivo against responses of single neurons in the rat spinal cord to microelectrophoretic application of NMDA with ID₅₀ values in the low milligram per kilogram i.v. range. They also inhibited pentylenetetrazol-, NMDA- and maximal electroshock-induced convulsions in mice with ED₅₀ values ranging from 8 to 100 mg/kg i.p. The duration of anticonvulsive action was rather short but was prolonged by the organic acid transport inhibitor probenecid (200 mg/kg). The agents tested represent a novel class of systemically active glycine_B antagonists with greatly improved bioavailability.