PHARMACOLOGICAL CHARACTERIZATION OF MDL-105,519, AN NMDA RECEPTOR GLYCINE SITE ANTAGONIST

MDL 105,519, arboxyethenyl)-3,6-dichloro-1H-indole-2-carboxylic acid, is a potent and selective inhibitor of [H-3]glycine binding to the NMD A receptor. MDL 105,519 inhibits NMDA (N-methyl-D-aspartate)-dependent responses including elevations of [H-3]N-[1,(2-thienyl)cyclohexyl]-pi peridine ([H-3]TCP) binding in brain membranes, cyclic GMP accumulatio n in brain slices, and alterations in cytosolic Ca2+ and Na+-Ca2+ curr ents in cultured neurons. Inhibition was non-competitive with respect to NMDA and could be nullified with D-serine. Intravenously administer ed MDL 105,519 prevented harmaline-stimulated increases in cerebellar cyclic GMP content, providing biochemical evidence of NMDA receptor an tagonism in vivo. This antagonism was associated with anticonvulsant a ctivity in genetically based, chemically induced, and electrically med iated seizure models. Anxiolytic activity was observed in the rat sepa ration-induced vocalization model, but muscle-relaxant activity was ap parent at lower doses. Higher doses impair rotorod performance, but we re without effect on mesolimbic dopamine turnover or prepulse inhibiti on of the startle reflex. This pattern of activities differentiates th is compound from 0,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine (M K-801) and indicates a lower psychotomimetic risk. (C) 1997 Elsevier S cience B.V.