Uncompetitive antagonists

Memantine is the first in a novel class of Alzheimer s disease medications acting a.o. on the NMDA receptor of the glutamatergic system. It also acts as an uncompetitive antagonist at different neuronal nicotinic receptors at potencies possibly similar to the NMDA receptor. Memantine is approved for treatment of moderate to severe Alzheimer s disease and its use is associated with a moderate decrease in clinical deterioration of the disease. Common adverse drug reactions (>1% of patients) include confusion, dizziness, drowsiness, headache, insomnia, agitation, and/or hallucinations. 

McClean, M., Chizh, B. A., Headley, P. M. Effects of NMDA receptor antagonists on nociceptive responses in vivo comparism of antagonists acting at the glycine site with uncompetitive antagonists, Amino Acids 1998, 14, 217-221. 

Amantadine Uncompetitive antagonist DuPont Launched Unknown (Teramoto etal., 1999)... 

Uncompetitive antagonism, form of inhibition (originally defined for enzyme kinetics) in which both the maximal asymptotic value of the response and the equilibrium dissociation constant of the activator (i.e., agonist) are reduced by the antagonist. This differs from noncompetitive antagonism where the affinity of the receptor for the activating drug is not altered. Uncompetitive effects can occur due to allosteric modulation of receptor activity by an allosteric modulator (see Chapter 6.4). 

The uncompetitive NMDA receptor antagonist ketamine has been available for clinical use as an anaesthetic for 40 years (Domino et al. 1965). Ketamine is effective in various animal models of hyperalgesia and allodynia and has been reported to have antinociceptive effects in some of these models at doses devoid of obvious side-effects. Others, however, have reported that the effects of ketamine are only seen at doses producing ataxia (see Parsons 2001 for review). Ketamine reportedly inhibits the area of secondary hyperalgesia induced by chemical (Park et al. 1995) or thermal stimuli (Ilkjaer et al. 1996 Warncke et al. 1997) and inhibits temporal siunmation of repeated mechanical (Warncke et al. 1997) and electrical stimuli (Arendtnielsen et al. 1995 Andersen et al. 

It is beheved that phenomena such as sensitization, tolerance and drug-dependence might also involve synaptic plasticity. In fact, numerous studies indicate that NMDA receptor antagonists block sensitization to amphetamine and cocaine as well as tolerance and dependence to ethanol and opioids in animal models (Trujillo and Akil 1991 Pasternak and Inturrisi 1995 Trujillo and Akil 1995 Mao 1999). Recent studies indicate that the uncompetitive NMDA receptor antagonists dextromethorphan, memantine and neramexane not only prevent the development of morphine tolerance, but also reverse estabhshed tolerance in the continuing presence of this opioid, prevent the expression of withdrawal symptoms in rats (Popik and Skolnick 1996 Popik and Danysz 1997 Popik and Kozela 1999 Houghton et al. 2001) and attenuate the expres-... 

Several lines of evidence have implicated NMDA receptor hypofunction in the pathophysiology of schizophrenia. The administration of certain, but not all, uncompetitive NMDA receptor antagonists exacerbates psychotic symptoms in schizophrenics and mimics schizophrenia in non-psychotic subjects (Coyle et al. 2003 Konradi and Heckers 2003). 

Holter SM, Danysz W, Spanagel R (2000) Novel uncompetitive N-methyl-D-aspartate (NMDA)-receptor antagonist MRZ 2/579 suppresses ethanol intake in long-term ethanol-experienced rats and generalizes to ethanol cue in drug discrimination procedure. J Pharmacol Exp Ther 292 545-552... 

Jones MW, McClean M, Parsons CG, Headley PM (2001) The in vivo significance of the varied channel blocking properties of uncompetitive NMDA receptor antagonists. Neuropharmacology 41 50-61... 

Parsons, C. G., Quack, G., Bresink, I., Baran, L., Przegalinski, E., Kostowski, W., Krzascik, P., Hartmann, S., Danysz, W. Comparison of the potency, kinetics, and voltage-dependency of a series of uncompetitive NMDA receptor antagonists in vitro with anticonvulsive and motor impairment activity in vivo, Neuropharmacology 1995, 34, 1239-1258. 

Parsons, C. G., Danysz, W, Bartmann, A., Spielmanns, P., Frankiewicz, T., Hesselink, M., Eilbacher, B., Quack, G. Amino-alkyl-cyclohexanes are novel uncompetitive NMDA receptor antagonists with strong voltage-dependency and fast blocking kinetics in vitro and in vivo characterization, Neuropharmacol. 1999b, 38, 85-108. 

Rogawski, M. A. Low affinity channel blocking (uncompetitive) NMDA receptor antagonists as therapeutic agents - towards an understanding of their favorable tolerability, Amino Acids 2000, 19, 133-149. 

Banerjee A, Schepmann D, Kurthwein J et al (2010) Synthesis and SAR studies of chiral non-racemic dexoxadrol analogues as uncompetitive NMDA receptor antagonists. Bioorg Med Chem 18(22) 7855-7867... 

Among promising candidates as antidotes against CNS intoxication by OP nerve agents, memantine (MEM) has been shown to pose both anti-excitotoxic and anti-epileptic properties. Memantine is an uncompetitive NMDA receptor antagonist, clinically used for the treatment of Alzheimer s disease, Parkinson s disease and spasticity, in the absence of serious side effects (Ozsuer et al, 2005 Lipton, 2005). From a series of rat in vivo experiments, it is evident that pre-administration of memantine significantly protects... 

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