NOVEL SYSTEMICALLY ACTIVE ANTAGONISTS OF THE GLYCINE SITE OF THE N-METHYL-D-ASPARTATE RECEPTOR - ELECTROPHYSIOLOGICAL, BIOCHEMICAL AND BEHAVIORAL CHARACTERIZATION

A series of novel tricyclic pyrido-phthalazine-dione derivatives was t ested for antagonistic effects at the strychnine-insensitive modulator y site of the N-methyl-D-aspartate (NMDA) receptor (glycine(B)). All c ompounds displaced [H-3]MDL-105,519 binding to rat cortical membranes with IC50 values of between 90 nM and 3.6 mu M. In patch-clamp experim ents, steady-state inward current responses of cultured hippocampal ne urons to NMDA (200 mu M, glycine 1 mu M) were antagonized by these sam e compounds with IC50 values of 0.14 to 13.8 mu M. The antagonism obse rved was typical for glycine(B) antagonists, i.e., they induced desens itization and their effects were not use or voltage dependent. Moreove r, increasing concentrations of glycine were able to decrease their ap parent potency. Much higher concentrations (>100 mu M) were required t o antagonize lpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-i nduced currents. They were potent, systemically active NMDA receptor a ntagonists in vivo against responses of single neurons in the rat spin al cord to microelectrophoretic application of NMDA with ID50 values i n the low milligram per kilogram i.v. range. They also inhibited penty lenetetrazol-, NMDA- and maximal electroshock-induced convulsions in m ice 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 organi c acid transport inhibitor probenecid (200 mg/kg). The agents tested r epresent a novel class of systemically active glycine(B) antagonists w ith greatly improved bioavailability.