NMDA receptors competitive antagonists

Figure 10.4 Structures of some antagonists at the various receptors for glutamate. CNQX is an AMPA antagonist but NQQX has greater selectivity. AP-5 is an NMDA receptor antagonist while MK-801 blocks the NMDA receptor channel (non-competitive)...

Memantine is a non-competitive antagonist oftheN-methyl-D-aspartate (NMDA) type of glutamate receptors, which are located ubiquitously throughout the brain. It regulates activity... 

Our first studies with compounds that alter Glu neurotransmission were not targeted at decreasing brain excitability. Rather, as noted above, we used the limbic hypermetabolism induced by non-competitive NMDA receptor antagonists to test whether an increase in the metabolic rate of these limbic structures... 

The mechanisms of action of phencyclidine and ketamine are complex (Gorelick Balster, 1995). The drugs are non-competitive antagonists at NMDA receptors, and also bind to associated phencyclidine/sigma opioid receptors. They also have agonist actions at dopamine receptors, complex interactions with both nicotinic and muscarinic acetylcholine receptors and poorly understood interactions with noradrenergic and serotonergic systems. These multiple actions may combine to produce delirium and psychotic reactions. 

Antagonists such as D-(-)-2-amino-5-phosphono-valeric acid (D-AP V), which competitively block NMDA receptors, cause numerous side-effects such as memory impairment, psychotomimetic effects, ataxia and motor dis-coordi-nation, since they also impair normal synaptic transmission. The challenge has therefore been to develop NMDA receptor antagonists that prevent the pathological activation of NMDA receptors but allow their physiological activation. 

A post-mortem study on the brains of alcohoUcs showed a modest increased binding for [3H]glutamate and [3H]CGP-39653—a competitive NMDA receptor antagonist (Freund and Anderson 1996). In humans with a history of alcohol abuse, an increase in immunoreactivity toward AMPA GluR2 and GluR3 subunits was also found (Breese et al. 1995). In rodents lacking functional... 

Papp M, Moryl E (1994) Antidepressant activity of non-competitive and competitive NMDA receptor antagonists in a chronic mild stress model of depression. Em J Pharmacol 263 1-7... 

The physiology and pathology of excitatory amino acid neurotransmission is described by C.G. Parsons, W. Danysz and W. ZieglgSnsberger. At present, there seems to be a consensus that competitive AMPA and N-methyl-o-aspar-tate (NMDA) receptor antagonists have a low chance of finding therapeutic applications. Antagonists showing moderate affinity and satisfactory selectivity for certain NMDA receptor subtypes seem to have a more favourable profile. 

Scheme 2 Examples for competitive NMDA receptor antagonists.

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