Subtype Selective NMDA Receptor Antagonists Research Articles

Subtype selective NMDA receptor antagonists induce recovery of synapses lost following exposure to HIV‐1 Tat

Neurocognitive disorders afflict approximately 20% of HIV-infected patients. HIV-1-infected cells in the brain shed viral proteins such as transactivator of transcription (Tat). Tat elicits cell death and synapse loss via processes initiated by NMDA receptor activation but mediated by separate downstream signalling pathways. Subunit selective NMDA receptor antagonists may differentially modulate survival relative to synaptic changes. Tat-evoked cell death was quantified by measuring propidium iodide uptake into rat hippocampal neurons in culture. The effects of Tat on synaptic changes were measured using an imaging-based assay that quantified clusters of the scaffolding protein postsynaptic density 95 fused to green fluorescent protein. Dizocilpine, a non-competitive NMDA receptor antagonist, inhibited Tat-induced synapse loss, subsequent synapse recovery and Tat-induced cell death with comparable potencies. Memantine (10 µM) and ifenprodil (10 µM), which preferentially inhibit GluN2B-containing NMDA receptors, protected from Tat-induced cell death with no effect on synapse loss. Surprisingly, memantine and ifenprodil induced synapse recovery in the presence of Tat. In contrast, the GluN2A-prefering antagonist TCN201 prevented synapse loss and recovery with no effect on cell death. Synapse loss is a protective mechanism that enables the cell to cope with excess excitatory input. Thus, memantine and ifenprodil are promising neuroprotective drugs because they spare synaptic changes and promote survival. These GluN2B-preferring drugs induced recovery from Tat-evoked synapse loss, suggesting that synaptic pharmacology changed during the neurotoxic process. NMDA receptor subtypes differentially participate in the adaptation and death induced by excitotoxic insult.

ChemInform Abstract: Parallel Synthesis of a Series of Subtype-Selective NMDA Receptor Antagonists.

Abstract A series of 1-(heteroarylthioalkyl)-4-benzylpiperidines was rapidly synthesized through the use of parallel synthesis to investigate the binding affinity for the NR1 a /2B receptor subtype.

Exposure to an enriched environment selectively increases the functional response of the pre‐synaptic NMDA receptors which modulate noradrenaline release in mouse hippocampus

We evaluated the impact of environmental training on the functions of pre-synaptic glutamatergic NMDA and alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) and nicotinic receptors expressed by hippocampal noradrenergic nerve terminals. Synaptosomes isolated from the hippocampi of mice housed in enriched (EE) or standard (SE) environment were labeled with [(3)H]noradrenaline ([(3)H]NA) and tritium release was monitored during exposure in superfusion to NMDA, AMPA, epibatidine or high K(+). NMDA -evoked [(3)H]NA release from EE hippocampal synaptosomes was significantly higher than that from SE synaptosomes, while the [(3)H]NA overflow elicited by 100 muM AMPA, 1 muM epibatidine or (9, 15, 25 mM) KCl was unchanged. In EE mice, the apparent affinity of NMDA or glycine was unmodified, while the efficacy was significantly augmented. Sensitivity to non-selective or subtype-selective NMDA receptor antagonists (MK-801, ifenprodil and Zn(2+) ions) was not modified in EE. Finally, the analysis of NMDA receptor subunit mRNA expression in noradrenergic cell bodies of the locus coeruleus showed that NR1, NR2A, NR2B and NR2D subunits were unchanged, while NR2C decreased significantly in EE mice as compared to SE mice. Functional up-regulation of the pre-synaptic NMDA receptors modulating NA release might contribute to the improved learning and memory found in animals exposed to an EE.

Kynurenic acid amides as novel NR2B selective NMDA receptor antagonists

A novel series of kynurenic acid amides, ring-enlarged derivatives of indole-2-carboxamides, was prepared and identified as in vivo active NR2B subtype selective NMDA receptor antagonists. The synthesis and SAR studies are discussed.

Differential roles of NR2A and NR2B-containing NMDA receptors in LTP and LTD in the CA1 region of two-week old rat hippocampus

The role of NMDA receptors in the induction of long-term potentiation (LTP) and long-term depression (LTD) is well established but which particular NR2 subunits are involved in these plasticity processes is still a matter of controversy. We have studied the effects of subtype selective NMDA receptor antagonists on LTP induced by high frequency stimulation (100 Hz for 1 s) and LTD induced by low frequency stimulation (1 Hz for 15 min) in the CA1 region of hippocampal slices from 14 day old Wistar rats. Against recombinant receptors in HEK293 cells NVP-AAM077 (NVP) was approximately 14-fold selective for NR2A vs NR2B receptors, whilst Ro 25-6981 (Ro) was highly selective for NR2B receptors. On NMDA receptor-mediated EPSCs from Schaffer collaterals in CA1 neurones, NVP and Ro both reduced the amplitude but differentially affected the time constant of decay. The data are compatible with the selective effect of NVP (0.1 μM) and Ro (4 μM) on native NR2A and NBR2B receptors, respectively. NVP reduced both LTP and LTD whereas Ro reduced only LTP. Thus, LTP was reduced by 63% at 0.1 μM NVP and almost completely at 0.4 μM whereas 5 μM Ro reduced LTP by 45%. These data are consistent with a role for both NR2A and NR2B in the induction of LTP, under our experimental conditions. In comparison, LTD was unaffected by Ro (5 μM) even in the presence of a glutamate uptake inhibitor threo-β-benzylaspartic acid (TBOA) to increase the concentration of glutamate at NR2B containing receptors. NVP (0.2–0.4 μM), however, produced a concentration dependent inhibition of LTD which was complete at 0.4 μM. The lack of effect of 0.1 μM NVP on LTD contrasts with its marked effect on LTP and raises the possibility that different NVP-sensitive NR2 subunit-containing NMDA receptors are required for LTP and LTD in this preparation.

Recent Advances in the Development of NR2B Subtype-Selective NMDA Receptor Antagonists

Over activation of the NMDA receptor complex has been implicated in a number of neurological conditions. The use of NMDA antagonists as therapeutic agents has been limited by serious cognitive and motor side effects. Significant efforts have been reported in the development of NR2B subtype-selective antagonists, which have shown efficacy without the side effects observed with nonspecific NMDA antagonists. Classical ifenprodil-like molecules containing benzyl- and phenylpiperidines attached to a phenol or an appropriate isostere by a linker have provided valuable chemical leads as potential therapeutic agents. In this review, recent efforts in the discovery and development of structurally unique NR2B subtype-selective NMDA antagonists that do not fit the classical "ifenprodil-like" pharmacophore will be discussed.

2-Styryl-pyridines and 2-(3,4-Dihydro-naphthalen-2-yl)pyridines as Potent NR1/2B Subtype Selective NMDA Receptor Antagonists

A series of 2-styryl-pyridines and 2-(3,4-dihydro-naphthalen-2-yl)-pyridines was prepared and evaluated as NR1/2B subtype selective NMDA receptor antagonists. The SAR developed in this series resulted in the discovery of high affinity antagonists that are selective (vs. ?1 and M1 receptors) and are active in vivo .

Subtype Selective NMDA Receptor Antagonists: Evaluation of Some Novel Alkynyl Analogues.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Subtype selective NMDA receptor antagonists: evaluation of some novel alkynyl analogues

A benzylpiperidine analogue with an acetylenic linker, 5-{3-[4-(4-fluorobenzyl)-piperidin-1-yl]-prop-1-ynyl}-1,3-dihydrobenzimidazol-2-one (3), was identified as a chemical lead with excellent activity at the NR1A/2B receptor (IC50=3 nM). Efforts to optimize this activity led to focused modifications around the structural motif of 3. The synthesis and SAR studies are discussed.

4‐(3,4‐Dihydro‐1H‐isoquinolin‐2yl)‐pyridines and 4‐(3,4‐Dihydro‐1H‐isoquinolin‐2‐yl)‐quinolines as Potent NR1/2B Subtype Selective NMDA Receptor Antagonists.

AbstractFor Abstract see ChemInform Abstract in Full Text.

1-Benzyloxy-4,5-dihydro-1H-imidazol-2-yl-amines, a novel class of NR1/2B subtype selective NMDA receptor antagonists.

Screening of the Roche compound depository led to the identification of (1-benzyloxy-4,5-dihydro-1H-imidazol-2-yl)-butyl amine 4, a structurally novel NR1/2B subtype selective NMDA receptor antagonist. The structure-activity relationships developed in this series resulted in the discovery of a novel class of potent and selective NMDA receptor blockers displaying activity in vivo.

2‐(3,4‐Dihydro‐1H‐isoquinolin‐2yl)‐pyridines as a Novel Class of NR1/2B Subtype Selective NMDA Receptor Antagonists.

AbstractFor Abstract see ChemInform Abstract in Full Text.

4-(3,4-Dihydro-1 H-isoquinolin-2yl)-pyridines and 4-(3,4-Dihydro-1 H-isoquinolin-2-yl)-quinolines as potent NR1/2B subtype selective NMDA receptor antagonists

A series of 4-(3,4-dihydro-1 H-isoquinolin-2yl)-pyridines and analogous quinolines was prepared and evaluated as NR1/2B subtype selective NMDA receptor antagonists. 2-Hydroxyalkylamino substitution combines high affinity with selectivity (vs α1 and M1 receptors) and activity in vivo.

4‐Aminoquinolines as a Novel Class of NR1/2B Subtype Selective NMDA Receptor Antagonists.

AbstractFor Abstract see ChemInform Abstract in Full Text.

2-(3,4-Dihydro-1 H-isoquinolin-2yl)-pyridines as a novel class of NR1/2B subtype selective NMDA receptor antagonists

Recently, we disclosed 4-aminoquinolines as structurally novel NR1/2B subtype selective NMDA receptor antagonists. We would now like to report our findings on structurally related pyridine analogues. The SAR developed in this series resulted in the discovery of high affinity antagonists which are selective (vs α1 and M1 receptors) and active in vivo.

Novel N1-(benzyl)cinnamamidine derived NR2B subtype-selective NMDA receptor antagonists

Novel ( E)- N 1-(benzyl)cinnamamidines were prepared and evaluated as NR2B subtype NMDA receptor ligands. Excellent affinity was achieved by appropriate substitution of either phenyl ring. The 2-methoxybenzyl compound 1h had ∼1000-fold lower IC 50 in NR2B than NR2A-containing cells. Replacement of the styryl unit by 2-naphthyl was well tolerated.

4-Aminoquinolines as a novel class of NR1/2B subtype selective NMDA receptor antagonists

Screening of the Roche compound library led to the identification of 4-aminoquinoline 4 as structurally novel NR1/2B subtype selective NMDA receptor antagonist. The SAR which was developed in this series resulted in the discovery of highly potent and in vivo active blockers.

Discovery of ( R)-1-[2-Hydroxy-3-(4-hydroxy-phenyl)-propyl]-4-(4-methyl-benzyl)-piperidin-4-ol: A Novel NR1/2B Subtype Selective NMDA Receptor Antagonist

Starting from Ro-25-6981 as a lead compound, highly potent and selective NR1/2B subtype selective NMDA receptor antagonists, with low activity at α 1 adrenergic receptors were developed.

Parallel synthesis of a series of subtype-selective NMDA receptor antagonists

A series of 1-(heteroarylthioalkyl)-4-benzylpiperidines was rapidly synthesized through the use of parallel synthesis to investigate the binding affinity for the NR1a/2B receptor subtype.