Pharmacological characterization of MDL 105,519, an NMDA receptor glycine site antagonist

Pharmacological characterization of MDL 105,519, an NMDA receptor glycine site antagonist MDL 105,519, ( E )-3-(2-phenyl-2-carboxyethenyl)-4,6-dichloro-1 H -indole-2-carboxylic acid, is a potent and selective inhibitor of ( 3 H)glycine binding to the NMDA receptor. MDL 105,519 inhibits NMDA ( N -methyl- d -aspartate)-dependent responses including elevations of ( 3 H) N -(1,(2-thienyl)cyclohexyl)-piperidine (( 3 H)TCP) binding in brain membranes, cyclic GMP accumulation in brain slices, and alterations in cytosolic Ca 2+ and Na + -Ca 2+ currents in cultured neurons. Inhibition was non-competitive with respect to NMDA and could be nullified with d -serine. Intravenously administered MDL 105,519 prevented harmaline-stimulated increases in cerebellar cyclic GMP content, providing biochemical evidence of NMDA receptor antagonism in vivo. This antagonism was associated with anticonvulsant activity in genetically based, chemically induced, and electrically mediated seizure models. Anxiolytic activity was observed in the rat separation-induced vocalization model, but muscle-relaxant activity was apparent at lower doses. Higher doses impair rotorod performance, but were without effect on mesolimbic dopamine turnover or prepulse inhibition of the startle reflex. This pattern of activities differentiates this compound from (5 R ,10 S )-(+)-5-methyl-10,11-dihydro-5 H -dibenzo( a , d )cyclohepten-5,10-imine (MK-801) and indicates a lower psychotomimetic risk. © 1997 Elsevier Science B.V. All rights reserved. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png European Journal of Pharmacology Elsevier

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Publisher
Elsevier
Copyright
Copyright © 1997 Elsevier Science B.V.
ISSN
0014-2999
DOI
10.1016/S0014-2999(97)00045-9
Publisher site
See Article on Publisher Site

Abstract

MDL 105,519, ( E )-3-(2-phenyl-2-carboxyethenyl)-4,6-dichloro-1 H -indole-2-carboxylic acid, is a potent and selective inhibitor of ( 3 H)glycine binding to the NMDA receptor. MDL 105,519 inhibits NMDA ( N -methyl- d -aspartate)-dependent responses including elevations of ( 3 H) N -(1,(2-thienyl)cyclohexyl)-piperidine (( 3 H)TCP) binding in brain membranes, cyclic GMP accumulation in brain slices, and alterations in cytosolic Ca 2+ and Na + -Ca 2+ currents in cultured neurons. Inhibition was non-competitive with respect to NMDA and could be nullified with d -serine. Intravenously administered MDL 105,519 prevented harmaline-stimulated increases in cerebellar cyclic GMP content, providing biochemical evidence of NMDA receptor antagonism in vivo. This antagonism was associated with anticonvulsant activity in genetically based, chemically induced, and electrically mediated seizure models. Anxiolytic activity was observed in the rat separation-induced vocalization model, but muscle-relaxant activity was apparent at lower doses. Higher doses impair rotorod performance, but were without effect on mesolimbic dopamine turnover or prepulse inhibition of the startle reflex. This pattern of activities differentiates this compound from (5 R ,10 S )-(+)-5-methyl-10,11-dihydro-5 H -dibenzo( a , d )cyclohepten-5,10-imine (MK-801) and indicates a lower psychotomimetic risk. © 1997 Elsevier Science B.V. All rights reserved.

Journal

European Journal of PharmacologyElsevier

Published: Apr 4, 1997

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