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 [3H]glycine binding to the NMDA receptor. MDL 105,519 inhibits NMDA (N-methyl-D-aspartate)-dependent responses including elevations of [3H]N-[1,(2-thienyl)cyclohexyl]-piperidine ([3H]TCP) binding in brain membranes, cyclic GMP accumulation in brain slices, and alterations in cytosolic CA2+ and NA(+)-CA2+ 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 (5R,10S)-(+)-5-methyl-10, 11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine (MK-801) and indicates a lower psychotomimetic risk.
Subject(s)
Excitatory Amino Acid Antagonists/pharmacology , Indoles/pharmacology , Receptors, Glycine/antagonists & inhibitors , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Animals , Anti-Anxiety Agents/pharmacology , Anticonvulsants/pharmacology , Calcium Channels/drug effects , Cells, Cultured , Cerebellum/metabolism , Cyclic GMP/metabolism , Excitatory Amino Acid Agonists/pharmacology , Excitatory Amino Acid Antagonists/metabolism , Indoles/metabolism , Ligands , Male , Mice , Mice, Inbred DBA , Motor Activity/drug effects , N-Methylaspartate/pharmacology , Phencyclidine/analogs & derivatives , Phencyclidine/metabolism , Rats , Rats, Inbred F344 , Rats, Wistar , Sodium Channels/drug effectsABSTRACT
A series of substituted 3-(2-carboxyindol-3-yl)propionic acids was synthesized and tested as antagonists for the strychnine-insensitive glycine binding site of the NMDA receptor. Chlorine, and other small electron-withdrawing substituents in the 4- and 6-positions of the indole ring, greatly enhanced binding and selectivity for the glycine site over the glutamate site of the NMDA receptor; one of the most potent compounds is 3-(4,6-dichloro-2-carboxyindol-3-yl)propionic acid (IC50 = 170 nM; greater than 2100-fold selective for glycine). The importance of a heteroatom NH and the enhancing effect of the propionic acid side chain were demonstrated and are consistent with previous results which suggest the presence of a pocket on the receptor which can accept an acidic side chain. Substitution of a sulfur at C3 led to the most potent compound 3-[(carboxymethyl)thio]-2-carboxy-4,6-dichloroindole (IC50 = 100 nM).