A-methyl-d-aspartate

NMD A receptors are selectively activated by A/-methyl-D-aspartate (NMD A) (182). NMD A receptor activation also requires glycine or other co-agonist occupation of an allosteric site. NMDAR-1, -2A, -2B, -2C, and -2D are the five NMD A receptor subunits known. Two forms of NMDAR-1 are generated by alternative splicing. NMDAR-1 proteins form homomeric ionotropic receptors in expression systems and may do so m situ in the CNS. Functional responses, however, are markedly augmented by co-expression of a NMDAR-2 and NMDAR-1 subunits. The kinetic and pharmacological properties of the NMD A receptor are influenced by the particular subunit composition. 

Compounds that have agonistic properties at glutamate or aspartate receptors are also CNS stimulants, readily cause convulsions, and presumably could also be employed as analeptics. Three separate excitatory amino acid receptor subtypes have been characterized pharmacologically, based on the relative potency of synthetic agonists. These three receptors are named for their respective prototypical agonists A/-methyl-D-aspartate [6384-92-5]... 

On the pathophysiological side, hyperactive nNOS has been implicated in A/-methyl-D-aspartate (NMDA)-receptor-mediated neuronal death in cerebrovascular-stroke. Some disturbances of smooth muscle tone within the gastrointestinal tract (e.g., gastroesophageal reflux disease) may also be related to an overproduction of NO by nNOS in peripheral nitrergic nerves. 

A -methyl-D-aspartate antagonists Dextromethorphan Limited number of drugs in this class are available for human use. Study findings have been negative. 

NMDAR. A-methyl-D-aspartate receptor—an ionotropic receptor for glutamate. It plays a critical role in synaptic plasticity mechanisms and thus is necessary for several types of learning and memory. 

Hata, N., Nishikawa, T., Umino, A., and Takahashi, K., Evidence for involvement of A-methyl-D-aspartate receptor in tonic inhibitory control of dopaminergic transmission in the rat medial frontal cortex, Neurosci. Lett., 120, 101, 1990. 

Schilstrom, B., Nomikos, G.G., Nisell, M., Hertel, P., Svensson, T.H. A-Methyl-D-aspartate receptor antagonism in the ventral tegmental area diminishes the systemic nicotine-induced dopamine release in the nucleus accumbens. Neuroscience. 82 781, 1998. 

Trujillo K., Akil H. Excitatory amino acids and drugs of abuse a role for A-methyl-D-aspartate receptors in drug tolerance, sensitization and physical dependence. Drug Alcohol Depend. 38 139, 1995. 

There is one additional drug approved for use in moderate to severe cases of AD memantine, marketed as Namenda. Memantine works by a distinct mechanism it has moderate affinity for A-methyl-D-aspartate (NMDA) receptors and is the only approved molecule for moderate to severe AD in this structural class. We should be grateful for the AD drugs that we do have but the fact is that there is an enormous need for far better ones. 

Coleman BR, Ratcliffe R, Oguntayo S, Shi X, Doctor B, Gordon R, Nambiar M. (2008) [-i-]-Huperzine A treatment protects against A-methyl-d-aspartate-induced seizure/status epilepticus in rats. Chembiol Interact 175 387-395. 

Amantadine was originally introduced as an antiviral compound (see Chapter 50), but it is modestly effective in treating symptoms of parkinsonism. It is useful in the early stages of parkinsonism or as an adjunct to levodopa therapy. Its mechanism of action in parkinsonism is not clear, but amantadine may affect dopamine release and reuptake. Additional sites of action may include antagonism at muscarinic and A-methyl-D-aspartate (NMDA) receptors. Adverse effects include nausea, dizziness, insomnia, confusion, hallucinations, ankle edema, and livedo reticularis. Amantadine and the anticholinergics may exert additive effects on mental functioning. 

In this chapter, we use the term cognitive enhancers to refer to two classes of pharmacological agents used in the treatment of Alzheimer s disease the cholinesterase inhibitors and the A-methyl-D-aspartate (NMDA) receptor antagonists. 

Thieno[2,3-, ]pyridinones, 159, act as inhibitors of [ H]glycine binding to the A -methyl-D-aspartate (NMDA) receptor. The effects of substitution patterns on reactivity have been studied, leading to thienopyridinones with activity comparable to known quinolinone antagonists <2006JME864>. 

ATP, adenosine 5 -triphosphate BH4, 5,6,7,8-tetrahydrobiopterin BMPO, 5- er -butoxycarbonyl-5-pyrroline A-oxide DBNBS, 3,5-dibromo-4-nitrosoben-zene sulfonate DEPMPO, 5-diethoxyphosphoryl-5-methyl-l-pyrroline A-ox-ide DMPO, 5,5-dimethyl- 1-pyrroline A-oxide EMPO, 5-ethoxycarbonyl-5-methyl-l-pyrroline A-oxide GSH, glutathione (y-L-glutamyl-L-cysteinyl-glycine) HRP, horseradish peroxidase MNP, 2-methyl-2-nitrosopropane MPO, myeloperoxidase NAD(P)H, fl-nicotinamine adenine dinucleotide (3 -phosphate), reduced from NMDA, A-methyl-D-aspartic acid PBN, N-tert-butyl-a-phenylnitrone PMN, polymorphonuclear lymphocyte POBN, a-(4-pyridyl-l-oxide)-A-fer -butylnitrone SOD, superoxide dismutase TEMP,... 

Djebaili M., De Bock F., Bailie V., Bockaert J., and Rondouin G. (2002). Implication of p53 and caspase-3 in kainic acid but not in A-methyl-d-aspartic acid-induced apoptosis in organotypic hippocampal mouse cultures. Neurosci. Lett. 327 1 1. 

Pepicelli O., Fedele E., Bonanno G., Raiteri M., Ajmone-Cat M. A., Greco A., Levi G., and Minghetti L. (2002). In vivo activation of A -methyl-D-aspartate receptors in the rat hippocampus increases prostaglandin E2 extracellular levels and triggers lipid peroxidation through cyclooxygenase-mediated mechanisms. J. Neurochem. 81 1028-1034. 

Bi H. and Sze C. I. (2002). A-methyl-D-aspartate receptor subunit NR2A and NR2B messenger RNA levels are altered in the hippocampus and entorhinal cortex in Alzheimer s disease. J. Neurol. Sci. 200 11-18. 

New D. R., Maggirwar S. B., Epstein L. G., Dewhurst S., and Gelbard H. A. (1998). HIV-1 Tat induces neuronal death via tumor necrosis factor-a and activation of non-A-methyl-D-aspartate receptors by a NFfcB-independent mechanism. J. Biol. Chem. 273 17852-17858. 

Albers G. W., Atkinson R. R, Kelley R. E., and Rosenbaum D. M. (1995). Safety, tolerability, and pharmacokinetics of the A-methyl-D-aspartate antagonist dextrorphan in patients with acute stroke. Dextrorphan Study Group. Stroke 26 254-258. 

Paul C. and Bolton C. (2002). Modulation of blood-brain barrier dysfunction and neurological deficits during acute experimental allergic encephalomyelitis by the A-methyl-D-aspartate receptor antagonist memantine. J. Pharmacol. Exp. Ther. 302 50-57. 

Rammes G., Rupprecht R., Ferrari U., Zieglgansberger W., and Parsons C. G. (2001). The A-methyl-D-aspartate receptor channel blockers memantine, MRZ 2/579 and other amino-alkyl-cyclohexanes antagonise 5-HT3 receptor currents in cultured HEK-293 and N1E-115 cell systems in a non-competitive manner. Neurosci. Lett. 306 81-84. 

Glutamate Relay neurons at all levels and some interneurons A-Methyl-D-aspartate (NMD A) NMDA 2-Amino-5-phosphonovalerate, CPP, MK-801 Excitatory t cation conductance, particularly Ca2+... 

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