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 [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.
Baron
B M
BM
Hoechst Marion Roussel, Cincinnati, OH 45215, USA. brucebaron@hmri.com
Harrison
B L
BL
Kehne
J H
JH
Schmidt
C J
CJ
van Giersbergen
P L
PL
White
H S
HS
Siegel
B W
BW
Senyah
Y
Y
McCloskey
T C
TC
Fadayel
G M
GM
Taylor
V L
VL
Murawsky
M K
MK
Nyce
P
P
Salituro
F G
FG
D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology; D000927:Anticonvulsants / Q000494:pharmacology; D015220:Calcium Channels / Q000187:drug effects; D002478:Cells, Cultured; D002531:Cerebellum / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000378:metabolism / Q000494:pharmacology*; D007211:Indoles / Q000378:metabolism / Q000494:pharmacology*; D008024:Ligands; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D009043:Motor Activity / Q000187:drug effects; D016202:N-Methylaspartate / Q000494:pharmacology; D010622:Phencyclidine / Q000031:analogs & derivatives / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D017208:Rats, Wistar; D018009:Receptors, Glycine / Q000037:antagonists & inhibitors*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D015222:Sodium Channels / Q000187:drug effects
D014151:Anti-Anxiety Agents; D000927:Anticonvulsants; D015220:Calcium Channels; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D007211:Indoles; D008024:Ligands; C101788:MDL 105519; D018009:Receptors, Glycine; D016194:Receptors, N-Methyl-D-Aspartate; D015222:Sodium Channels; D016202:N-Methylaspartate; C012058:tenocyclidine; D006152:Cyclic GMP; D010622:Phencyclidine