NMDA-receptor antagonist

Antidepressants are used in the treatment of neuropathic pain and headache. They include the classic tricyclic compounds and are divided into nonselective nor-adrenaline/5-HT reuptake inhibitors (e.g., amitriptyline, imipramine, clomipramine, venlafaxine), preferential noradrenaline reuptake inhibitors (e.g., desipramine, nortriptyline) and selective 5-HT reuptake inhibitors (e.g., citalopram, paroxetine, fluoxetine). The reuptake block leads to a stimulation of endogenous monoaminer-gic pain inhibition in the spinal cord and brain. In addition, tricyclics have NMDA receptor antagonist, endogenous opioid enhancing, Na+ channel blocking, and K+ channel opening effects which can suppress peripheral and central sensitization. Block of cardiac ion channels by tricyclics can lead to life-threatening arrhythmias. The selective 5-HT transporter inhibitors have a different side effect profile and are safer in cases of overdose [3]. 

Antagonists selective for kainate receptors are not available yet. The non-NMDA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) blocks AMPA as well as kainate receptors. Nevertheless, compounds like GYKI53655, which acts as a noncompetitive antagonist of AMPA receptors and completely blocks AMPA receptor function at certain concentrations at which no antagonistic effect on kainate receptors is discernible, has been used to demonstrate the kainate receptor-mediated currents in neurons. 

Kemp JA, Kew JNC, Gill R (1999) NMDA receptor antagonists and their potential as neuroprotective agents, chapter 16 Ionotropic glutamate receptors in the CNS. Springer Verlag... 

Although dirhodium(II) carboxamidates are less reactive toward diazo decomposition than are dirhodium carboxylates, and this has limited their uses with diazomalonates and phenyldiazoacetates, the azetidinone-ligated catalysts 11 cause rapid diazo decomposition, and this methodology has been used for the synthesis of the cyclopropane-NMDA receptor antagonist milnacipran (17) and its analogs (Eq. 2) [10,58]. In the case of R=Me the turnover number with Rh2(45-MEAZ)4 was 10,000 with a stereochemical outcome of 95% ee. 

Toggas SM, Masliah E, Mucke L (1996) Prevention of HIV-1 gpl20-induced neuronal damage in the central nervous system of transgenic mice by the NMDA receptor antagonist memantine. Brain Res 706 303-307... 

On the basis of the events that occur in pain and LTP, it is easy to see how the actions of glutamate relate to the excessive firing of neurons — as yet no NMDA receptor antagonist has been tested in human epilepsy. 

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)...

Dickenson, AH (1990) A cure for wind-up NMDA receptor antagonists as potential analgesics. Trends Pharm. Sci. 11 307-309. 

Amantadine (Symmetrel ) NMDA-receptor antagonist that blocks glutamate transmission, promotes DA release, and blocks Ach Start with 1 00 mg daily at breakfast after 1 week, add 1 00 mg daily in the early afternoon decrease dose as creatinine clearance decreases less than... 

The basal forebrain is an important way station in the activation of the cerebral cortex from the reticular activating system. AMPA and NMDA injections into the basal forebrain increase wakefulness and reduce sleep (Cape Jones, 2000 Manfridi et al, 1999), effects that are blocked by AMPA and NMDA receptor antagonists (Manfridi et al, 1999). The excitatory cortical projections of the basal forebrain have long been considered purely cholinergic, but many basal forebrain neurons that project to the cortex are now known to contain Glu, which may function as a co-transmitter or even as the primary excitatory neurotransmitter (Manns et al, 2001). The basal forebrain also affects vigilance via synapses to HCT cells in the lateral hypothalamus some of these synapses are glutamatergic (Henny Jones, 2006). 

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... 

Hanania, T. and Zahniser, N.R., Locomotor activity induced by noncompetitive NMDA receptor antagonists versus dopamine transporter inhibitors opposite strain differences in inbred long-sleep and short-sleep mice, Alcohol Clin. Exp. Res., 26, 431, 2002. 

Shoaib, M., Schindler, C.W., Goldberg, S.R., Pauly, J.R. Behavioural and biochemical adaptations to nicotine in rats influence of MK801, an NMDA receptor antagonist. Psychopharmacology (Berlin). 134 121, 1997. 

Ida I., Aami T., Kuribara H. Inhibition of cocaine sensitization by MK-801 a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist evaluation by ambulatory activity in mice. Jpn. J. Pharmacol. 69 83, 1995. 

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