A-Methyl-o-aspartate receptor

Physiological sites proposed for nitric oxide action include the immune system, where nitric oxide acts as a cytostatic agent, is tumoricidal, and can inhibit viral replication. In the cardiovascular system, nitric oxide is the biological mediator of vasodilator responses to agents such as acetylcholine and bradykinin, which act as receptors on endothelial cells to activate NOS and stimulate nitric oxide production. Diffusible nitric oxide then activates guanylate cyclase in vascular smooth muscle cells, leading to the production of cyclic guano-sine monophosphate (GMP) and vasodilation. In the brain, stimulation of A-methyl-o-aspartate receptors on... 

At micromolar concentrations opioids cause an increase in the cell membrane threshold, shortened action potentials, and inhibition of neurotransmitter release. At nanomolar concentrations opioid agonists are excitatory and prolong the action potential via the stimulatory G proteins, which act on the adenylate cyclase/cAMP system and on protein kinase A-dependent ion channels. Tolerance is proposed to be the result of an increase in the association of opioid receptors to stimulatory G proteins, to an activation of A-methyl-o-aspartate receptors via protein kinase C, and calmodulin-dependent increases in cytosolic calcium, resulting in cellular hyperexcitability. 

The substituted imidazo-thiazole, dexamisole, has antidepressant properties and its isomer, levamisole, possesses anthelmintic and immunostimulant properties. Enantiomers of HA-966 (3-amino-l-hydroxypyrrolid-2-one) exhibit distinct central nervous system effects (+)-HA-966 is a selective glycine/A-methyl-o-aspartate receptor antagonist, but (-)-HA-966 is a potent i-butyrolactone-Uke sedative." A comparison of (+) and (-)-3-methoxycypro-heptadine shows that aU of the anticholinergic activity of the ( )-3-methoxycyproheptadine resides solely in the dextrorotatory enantiomer, while the antiserotonin activity resides in the levorotatory enantiomer." ... 

Glutamic acid Most neurons in the brain are excited by glutamic acid. Subtypes of glutamate receptors include the NMDA (A-methyl-o-aspartate) receptor, which is blocked by phencyclidine (PCP) and ketamine. NMDA receptors appear to play a role in synaptic plasticity related to learning and memory. Excessive activation of NMDA receptors following neuronal injury may be responsible for cell death. Glutamate metabotropic receptor activation can result in G-protein-coupled activation of phospholipase C or inhibition of adenylyl cyclase. 

Prakash C, Cui D, Potchoiba MJ, Butler T. Metabolism, distribution and excretion of a selective A-methyl-o-aspartate receptor antagonist, traxoprodil, in rats and dogs. Drug Metab Dispos 2007a 35 1350—1364. 

There are three types of glutamate reeeptors A-methyl-o-aspartate receptors, a-amino-3-hydroxyl-5-methyl-4-isoxazole-propionic acid receptors and kainate reeeptors. Each has several subtypes. 

Ndountse, L. T. Chan, H. M. Methylmercury increases A -methyl-o-aspartate receptors on human SH-SY 5Y neuroblastoma cells leading to neurotoxicity. Toxicology 2008, 249, 251-255. 

Regulation of A -Methyl-o-Aspartate Receptors by Spermine and Ifenprodil... 

Some derivatives of adamantane with antagonist or agonist effects have also been synthesized. For instance, monocationic and dicationic adamantane derivatives block the a-amino-3-hydroxy-5-methylisoxazole -propionic acid (AMPA) receptors, A-methyl-o-aspartate (NMDA) receptors [134—136] and 5-hydroxytryptamine (5-HT3) receptors [137]. 

Some drags block sodium channels, while others act on the GABA system. They enhance the GABA-dependent CNS inhibition. They also change the innacellular ratio of calcium and potassium ion concentrations, and block the A-methyl-o-aspartate (NMDA) receptor responsible for high-frequency discharges that appear during epilepsy. 

Excitatory neurotransmitters also may be involved in the appearance of epilepsy, since the bursting activity typically seen during epileptic discharges may be due in part to the action of glutamate acting on A-methyl-o-aspartate (NMDA) receptor channels to produce depolarization. It is likely that a major part of the anticonvulsant activity of felbamate involves blockade of the NMDA receptor. Table 32.2 summarizes the most likely mechanism of action associated with available anticonvulsant drugs. 

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. 

Lehmann, J., Hutchison, A.J., McPherson, S.E., Mondadori, C., Schmutz, M., Sinton, C.M., Tsai, C., Murphy, D.E., Steel, D.J., and Williams, M., CGS 19755, a selective and competitive A-methyl-o-aspartate-type excitatory amino acid receptor antagonist, J. Pharmacol. Exp. Ther, 246, 65, 1988. 

Muller, W., Kipfer, P., Lowe, D.A., and Urwyler, S., Syntheses of biphenyl analogues of AP7. a new class of competitive A-methyl-o-aspartate (NMDA) receptor antagonists. Helv. Chim. Acta. 78. 2026, 1995. 

Acylpolyamines are potent neurotoxins that have been shown to inhibit calcium-ion channels and selectively block glutamate, NMDA (A-methyl-o-aspartate), or AMPA (a-amino-3-hydroxy-5-methylisoxazol-4-propionate) receptors, which is probably the basis of their insecticidal properties. As a result, acylpolyamines have received considerable attention as tools for studying neurotransmitter function and may be of therapeutic... 

Glutamate acts on A-methyl-o-aspartate (NMDA) receptors in the brain. Drugs have been developed to block these receptors. An example is memantine. 

Acamprosate is a competitive inhibitor of the A-methyl-o-aspartate (NMDA)-type glutamate receptor that is proposed to normalize the dysregulated neurotransmission associated with chronic ethanol intake and thereby to attenuate one of the mechanisms that lead to relapse. In several European studies, acamprosate has been shown to promote abstinence either alone or in combination with naltrexone. 

Aquopentacyanoferrate(II), [Fe"H20(CN)5] ", one of the photo degradation products of vasodilator and nitric oxide donor nitroprusside, is a highly potent, competitive, and selective N-methyl-o-aspartate receptor antagonist (Neijt et al. 2001). It blocked N-methyl-D-aspartate-induced depolarisation in rat cortical slices at submicromolar concentrations, whereas responses to a-amino-3-hy-droxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainate were not affected. 

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