An N-methyl-D-aspartate receptor channel blocker with neuroprotective activity (original) (raw)
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Neuroprotection by novel antagonists at the NMDA receptor channel and glycineB sites
European Journal of Pharmacology, 1998
Glutamate may act via an N-methyl-D-Aspartate (NMDA)-sensitive receptor site to destroy cholinergic neurons within the nucleus basalis magnocellularis in age-associated neurodegenerative diseases. Multiple interesting properties of the NMDA receptor are relevant to its excitotoxic actions, e.g., glutamate is ineffective unless a glycine (gly) modulatory site is also occupied. Thus, the antagonism of glutamate receptor-related toxicity by blockade of either the NMDA-sensitive recognition site or the gly binding site may therefore have therapeutic applications. The current study investigated the ability of four novel noncompetitive antagonists at these two sites: one NMDA open channel antagonist (MRZ 2/579: 1-amino-1,3,3,5,5-pentamethyl-cyclohexane hydrochloride), and three glyB receptor antagonists (MRZ 2/570: 8-bromo-4-hydroxy-1-oxo-1,2-dihydropyridaziono [4,5-beta] quinoline-5-oxide choline salt; MRZ 2/57: 8-fluoro-4-hydroxy-1-oxo-1,2-dihydropyridaziono [4,5-beta] quinoline-5-oxide choline; MRZ 2/576: 8-chloro-4-hydroxy-1-oxo-1,2-dihydropyridaziono [4,5-beta] quinoline-5-oxide choline) administered acutely, to provide neuroprotection from a NMDA receptor agonist within the nucleus basalis magnocellularis of young rats. Injection of NMDA into the nucleus basalis magnocellularis significantly decreased cortical choline acetyltransferase activity. Acute administration (i.p.) of MRZ 2/579, 2/570, 2/571 and 2/576 provided significant neuroprotection from NMDA.
Journal of Neural Transmission, 2007
The fact that potent NMDA receptor channel blockers produce phencyclidine-like psychotropic symptoms in man and rodents implies that uncompetitive antagonism of NMDA receptors may not be a promising therapeutic approach. However, recent data indicate that agents with moderate affinity such as memantine and neramexane (MRZ 2=579) are useful therapeutics due to their strong voltage-dependency and rapid unblocking kinetics. Merz has developed a series of novel uncompetitive NMDA receptor antagonists based on an amino-alkylcyclohexane structure. These compounds displaced [ 3 H]-MK-801 binding to rat cortical membranes with K i values between 1 and 100 mM and inward current responses of cultured hippocampal neurons to NMDA were antagonized in a strongly voltage-dependent manner with rapid blocking= unblocking kinetics. Three of these compounds, with similar biophysical properties to memantine, were chosen for development. MRZ 2=759 (1ethenyl-3,3,5,5-tetramethyl-cyclohexylamine), 2=1010 (1,3,3,5-tetramethyl-6-azabicyclo[3.2.1]octane) and 2=1013 (8,8,10,10-tetramethyl-1-azaspiro[5.5] undecane) displaced [ 3 H]-MK-801 binding with K i values of 1.18, 2.59 and 3.64 mM, respectively. They were similarly potent against NMDA-induced currents in hippocampal neurons -IC 50 values of 1.51, 3.06 and 2.20 mM, respectively. In line with their moderate affinity, all were voltage-dependent (d ¼ 0.86, 0.96 and 0.89, respectively) and fast, open-channel blockers (k on 7.90, 1.70 and 2.60 Â 10 4 M À1 sec À1 , k off 0.13, 0.12 and 0.24 sec À1 , respectively). These compounds are also NMDA receptor antagonists in the CNS following systemic administration and have good therapeutic indices in a variety of in vivo behavioural models where glutamate is known to play a pivotal role. In view of their relatively low affinity and associated rapid kinetics, they should prove to be useful therapeutics in a wide range of CNS disorders.
Neuropharmacology, 1999
The present study characterized the in vitro NMDA receptor antagonistic properties of novel amino-alkyl-cyclohexane derivatives and compared these effects with their ability to block excitotoxicity in vitro and MES-induced convulsions in vivo. The 36 amino-alkyl-cyclohexanes tested displaced [3H]-(+)-MK-801 binding to rat cortical membranes with K(i)s between 1.5 and 143 microM. Current responses of cultured hippocampal neurones to NMDA were antagonized by the same compounds with a wide range of potencies (IC50s of 1.3-245 microM, at -70 mV) in a use- and strongly voltage-dependent manner (delta 0.55-0.87). The offset kinetics of NMDA receptor blockade was correlated with equilibrium affinity (Corr Coeff. 0.87 P < 0.0001). As an example, MRZ 2/579 (1-amino-1,3,3,5,5-pentamethyl-cyclohexane HCl) had similar blocking kinetics to those previously reported for memantine (K(on) 10.67 +/- 0.09 x 10(4) M(-1) s(-1), K(off) 0.199 +/- 0.02 s(-1), K(d) = K(off)/K(on) = 1.87 microM c.f. IC50 of 1.29 microM). Most amino-alkyl-cyclohexanes were protective against glutamate toxicity in cultured cortical neurones (e.g. MRZ 2/579 IC50 2.16 +/- 0.03 microM). Potencies in the three in vitro assays showed a relatively strong cross correlation (all corr. coeffs. > 0.72, P < 0.0001). MRZ 2/579 was also effective in protecting hippocampal slices against 7 min. hypoxia/hypoglycaemia-induced reduction of fEPSP amplitude in CA1 with an EC50 of 7.01 +/- 0.24 microM. MRZ 2/579 showed no selectivity between NMDA receptor subtypes expressed in Xenopus oocytes but was somewhat more potent than in patch clamp experiments-IC50s of 0.49 +/- 0.11, 0.56 +/- 0.01 microM, 0.42 +/- 0.04 and 0.49 +/- 0.06 microM on NR1a/2A /2B, /2C and 2/D, respectively. In contrast, memantine and amantadine were both 3-fold more potent at NR1a/2C and NR1a/2D than NR1a/2A receptors. All Merz amino-alkyl-cyclohexane derivatives inhibited MES-induced convulsions in mice with ED50s ranging from 3.6 to 130 mg/kg i.p. The in vivo and in vitro potencies correlated indicating similar access of most compounds to the CNS. MRZ 2/579 administered at 10 mg/kg resulted in peak plasma concentrations of 5.3 and 1.4 microM following i.v. and p.o. administration respectively, which then declined with a half life of around 170-210 min. Analysis of A.U.C. concentrations indicates a p.o./i.v. bioavailability ratio for MRZ 2/579 of 60%. MRZ 2/579 injected i.p. at a dose of 5 mg/kg resulted in peak brain extracellular fluid (ECF) concentrations of 0.78 microM (brain microdialysates). Of the compounds tested MRZ 2/579, 2/615, 2/632, 2/633, 2/639 and 2/640 had affinities, kinetics and voltage-dependency most similar to those of memantine and had good therapeutic indices against MES-induced convulsions. We predict that these amino-alkyl-cyclohexanes, which all had methyl substitutions at R1, R2, and R5, at least one methyl or ethyl at R3 or R4 and a charged amino-containing substitution at R6, could be useful therapeutics in a wide range of CNS disorders proposed to involve disturbances of glutamatergic transmission.
The Journal of pharmacology and experimental therapeutics, 2000
A novel series of N-substituted 4-ureido-5,7-dichloro-quinolines were synthesized to contain pharmacophores directed at voltage-sensitive sodium channels (VSNaCs) and N-methyl-D-aspartate (NMDA) receptors. These compounds were shown to act in a use-dependent manner as antagonists of VSNaCs and to act as selective competitive antagonists at the strychnine-insensitive glycine recognition site of NMDA receptors. These agents had little or no effect on alpha-adrenergic receptors, other glutamate receptors, or sites other than the glycine site on the NMDA receptor, and did not block voltage-sensitive calcium channels in vitro. In vivo, the compounds were active in preventing or reducing the signs and symptoms of neurohyperexcitability and had anxiolytic properties. Unlike benzodiazepines, N-substituted 4-ureido-5, 7-dichloro-quinolines showed little interaction with the sedative effects of ethanol, but were effective in controlling ethanol withdrawal seizures. The combined actions of the...
Chemical Biology & Drug Design, 2012
The N-methyl-D-aspartic acid (NMDA) receptors are a group of ionotropic glutamate receptors that plays an important role in different physiological functions, including the neuronal development, synaptic plasticity, learning, and memory (1). NMDA receptor is composed of multiple protein subunits, GLUN1, GLUN2 (A-D), and GLUN3 (A-B) in different combinations. In general, the physiological receptor is a heteromer, containing GLUN1 subunit with one or two GLUN2 subunits, but different compositions may occur (2-4). Therefore, depending on the receptor composition both the electrophysiological and pharmacological properties may vary (4). Due to its role, the over-stimulation of NMDA receptor has been implicated in several pathological conditions, involving neuronal death and degeneration (e.g., thrombo-embolic stroke, traumatic head injury, Parkinson's, Huntington's, and Alzheimer's diseases). Therefore, this pathological role has driven the search for NMDA receptor antagonists as a promising therapy (5-8). Currently, the use of NMDA receptor antagonists for acute and chronic neuronal diseases
Journal of Neurochemistry, 2002
The object of this investigation was to determine whether glutamate uptake affects the apparent potency of the competitive antagonists DL-2-amino-5-phosphonovalerate and CGS-19755 in blocking NMDA receptor-mediated neurotoxicity . In astrocyte-rich rat cortical cultures we observed that DL-2-amino-5-phosphonovalerate and CGS-19755 were 24 and 16 times more potent against NMDA than against glutamate-induced toxicity . In contrast, DL-2-amino-5-phosphonovalerate was equipotent against the two agonists in astrocyte-poor cultures, in which dendrites are directly exposed to the extracellular medium . With the noncompetitive NMDA antagonist MK-801, similar potencies were observed against glutamate (212 --16 n" and against NMDA (155 9 n" neurotoxicity . These results may be explained if we assume that the neuronal cell body is less susceptible than the dendrites to NMDA receptor-mediated toxicity, and that the action of glutamate in astrocyte-rich cultures is confined to the cell body. In this case, one would expect that higher concentrations of glutamate would be needed to produce toxicity in astrocyte-rich cultures, and that higher concentrations of competitive antagonists would be needed to overcome this toxicity . Our observations help explain the pharmacology of the competitive NMDA antagonists against NMDA receptor-mediated neurotoxicity but also suggest the possibility that, because the cell body and dendrites may be distinct sites for neurotoxicity, they might also involve different mechanisms of toxicity . Key Words : Glutamate uptake-DL-2-Am ino-5-phosphonovalerate-CGS-19755-MK-801-NMDA receptor-Excitotoxicity-Stroke -Astrocytes . J . Neurochem. 63, 879-885 (1994) .
A series of novel tricyclic pyrido-phthalazine-dione derivatives was tested for antagonistic effects at the strychnine-insensitive modulatory site of the N-methyl-D-aspartate (NMDA) receptor (glycine B ). All compounds displaced [ 3 H]MDL-105,519 binding to rat cortical membranes with IC 50 values of between 90 nM and 3.6 M. In patch-clamp experiments, steady-state inward current responses of cultured hippocampal neurons to NMDA (200 M, glycine 1 M) were antagonized by these same compounds with IC 50 values of 0.14 to 13.8 M. The antagonism observed was typical for glycine B antagonists, i.e., they induced desensitization and their effects were not use or voltage dependent. Moreover, increasing concentrations of glycine were able to decrease their apparent potency. Much higher
Neuropharmacology, 1997
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 PM, 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 NRla/NR2A and NRla/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 (mKr values: L-701,324 = 0.005 PM on both assemblies; L-695,902 = 4.37 and 3.7 PM on NRla/NR2A and NRla/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. Copyright 0 1996