The effects of five glycine site antagonists were comparatively examined on maximal and plateau currents evoked by 200 microM N-methyl-D-aspartate (NMDA) in the presence of 1 microM glycine in cultured cerebrocortical cells of the rat using whole-cell patch-clamp technique. 5,7-Dichlorokynurenic acid, ACEA-1021 (5-nitro-6,7-dichloro-quinoxalinedione), L-695,902 (methyl 7-chloro-4-hydroxy 2(1H)-quinolone-3-carboxylate), LY-294,619 (5,7-dichloro-3-(4-hydroxphenyl)-4-hydroxyquinolin-2(1H)-one ) and RPR-104,632 (2-(3-bromo-benzyl)-6,8-dichloro-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxide-3-carboxylic acid) caused concentration-dependent inhibition of NMDA-activated currents. However, antagonists showed different relative efficacies to block peak currents and plateau currents, characterised by the following IC50 ratios: L-695,902: 0.98; RPR-104,632: 1.06; ACEA-1021: 1.69; LY-294,619: 1.71; and 5,7-dichlorokynurenic acid: 3.42. Our findings indicate a heterogeneity of glycine site antagonists in affecting NMDA receptor desensitisation, and suggest potential differences in their pharmacologies.

01 Jan 1996·NeuropharmacologyQ2 · MEDICINE

Electrophysiological characterisation of the antagonist properties of two novel NMDA receptor glycine site antagonists, L-695,902 and L-701,324

Q2 · MEDICINE

Article

Author: Tony Priestley ; Raymond G Hill ; Petra Laughton ; John A Kemp ; Alison J Macaulay

The pharmacological effects of two novel N-methyl-D-aspartate (NMDA) receptor glycine site antagonists, L-701,324 and L-695,902 were examined on whole-cell voltage-clamped cells and compared to a prototypic antagonist, 7-chlorokynurenic acid. Both L-701,324 and L-695,902 non-competitively antagonised NMDA responses elicited in rat cultured cortical neurones, this was shown to be due to a competitive interaction at the glycine co-agonist site on the receptor complex (Kb values: 19 nM and 2.6 microM, respectively). Inhibition curves for the antagonism of responses to combined applications of NMDA and glycine showed that both antagonists were devoid of any intrinsic activity i.e. "full" antagonists and were, therefore, capable of completely abolishing inward currents. Despite this fact, both of these novel antagonists apparently modulated glutamate affinity for its recognition site-a property hitherto associated only with glycine site partial agonists. Human recombinant NMDA receptors comprising NR1a/NR2A and NR1a/NR2B subunits expressed in mouse fibroblast cells were also used to determine whether L-701,324 and L-695,902 were capable of discriminating between subtypes of NMDA receptor. Inhibition curves to each antagonist showed no difference in affinity for either of these subunit assemblies (mK1 values L-701,324 = 0.005 microM on both assemblies; L-695,902 = 4.37 and 3.7 microM on NR1a/NR2A and NR1a/NR2B, respectively). Kinetic analysis of the off-rates of antagonism with L-701,324 revealed that the high affinity of this compound compared to 7-chlorokynurenic acid were attributable to an exceptionally slow dissociation of the antagonist from the receptor.

01 Aug 1995·European Journal of Pharmacology: Molecular PharmacologyQ3 · MEDICINE

Allosteric modulation of the glutamate site on the NMDA receptor by four novel glycine site antagonists

Q3 · MEDICINE

Article

Author: Michael Rowley ; Paul D. Leeson ; Ian M. Mawer ; Janusz J. Kulagowski ; Sarah Grimwood ; Alan C. Foster

Using radioligand binding studies, we have investigated the binding properties of four 4-hydroxy-2-quinolones, a novel series of selective antagonists for the glycine site on the N-methyl-D-aspartate (NMDA) receptor. L-701,324, L-703,717, L-698,532 and L-695,902 inhibited [3H]L-689,560 (glycine site antagonist) binding to rat cortex/hippocampus P2 membranes with IC50 values of 1.97, 4.47, 209 and 6448 nM, respectively, whilst also inhibiting non-equilibrium [3H]dizocilpine binding to the NMDA receptor ion-channel. All four compounds partially inhibited L-[3H]glutamate (approximately 50% inhibition; agonist) binding and enhanced [3H]cis-4-phosphonomethyl-2-piperidine carboxylate ([3H]CGS-19755; 41-81% enhancement; 'C-5' antagonist) and [3H]3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonate ([3H]CPP; 28-66% enhancement; 'C-7' antagonist) binding to the glutamate recognition site of the NMDA receptor with EC50 values similar to those observed for [3H]L-689,560 binding. These results provide further evidence for allosteric interactions between the glutamate and glycine recognition sites of the NMDA receptor complex, and as the 4-hydroxy-2-quinolones are 'full' antagonists at the glycine site, indicate that these interactions are not caused by the intrinsic activity of a compound.

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Indication	Highest Phase	Country/Location	Organization	Date
Epilepsy	Discovery	US	Merck & Co., Inc.	-

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