NMDA channel blockers

The NRl family is composed of one subunit with nine different alternatively spliced variants. Block by NMDA channel blockers such as ketamine, MK-801 and phencyclidine is affected by which splice variant of the NRl subunit is involved, probably because the NRl splice variant affects the kinetics of channel activation (the effectiveness of any channel blocker being dependent on how much the channel is open). The glycine binding site is on the NRl subunit and the glutamate binding site is on the NR2 and NR3 subunits. 

The evidence given above is probably sufficient to consider glutamate antagonists as plausible neuroprotective treatment of ALS. Unfortunately, most clinical trials with glutamate antagonists completed to date have not been encouraging. Dextromethorphan (NMDA channel blocker) showed no benefit (Blin et al. 1996 Gredal et al. 1997). 

Dextromethorphan and its O-demethylated metabolite dextrorphan (morphinans), are also low to medium affinity NMDA channel blockers. The former has been in clinical use as an antitussive for about 40 years and could therefore be considered as a very safe drug (Bern et al., 1992). 

Houghton, A. K., Parsons, C. G., Headley, P. M. Mrz2/576, a fast kinetic NMDA channel blocker, reduces the development of morphine tolerance in awake rats, Pain 2001, 91, 201-207. 

Glutamate receptor antagonists - NMDA channel blocker cerestat,... 

Remacemide hydrochloride is a low-affinity, noncompetitive N-methyl-D-aspartate (NMDA) channel blocker that has been used in epilepsy, Parkinson s disease, Huntington s chorea, and nenroprotection after stroke. Its pharmacology, clinical pharmacology, uses, and adverse effects and interactions have been reviewed (1,2). 

These results support the view that the blockade of NMDA receptor could be of therapeutic benefit, and, in this respect, glycine antagonists appear to be extremely effective. Furthermore, GV 150526 lacks the adverse behavioral effects in rats observed for both competitive NMDA antagonists and NMDA channel blockers neither... 

Psychotomimetic Drugs. Figure 2 Chemical structures of the dissociative anesthetics phencyclidine (PCP) and ketamine. Both are arylcycloalkylamine derivatives that are open channel blockers of the NMDA channel. 

The ion-channel blocking mechanism has been widely tested and found to be important in both pharmacology and physiology. Examples are the block of nerve and cardiac sodium channels by local anesthetics, or block of NMDA receptor channels by Mg2+ and the anesthetic ketamine. The channel-block mechanism was first used quantitatively to describe block of the squid axon K+ current by tetraethylammonium (TEA) ions. The effects of channel blockers on synaptic potentials and synaptic currents were investigated, particularly at the neuromuscular junction, and the development of the single-channel recording technique allowed channel blockages to be observed directly for the first time. 

Hypofunction of NMDA receptors may contribute to the endophenotype of schizophrenia. The hypothesis that hypofunction of a subpopulation of NMDA receptors contributes to the pathophysiology of schizophrenia has gained considerable support over the last decade (see Fig. 54-1). The dissociative anesthetics including phencyclidine (PCP) and ketamine when introduced clinically 40 years ago were noted to produce a syndrome that was difficult to distinguish from schizophrenia. These agents act as noncompetitive open-channel blockers of the NMDA receptor. 

While all of these events are interconnected, the two most critical are neuronal rapid influx of Ca2+ and activation of nNOS, both which trigger all downstream events. Therefore, directly blocking the toxic effects of glutamate /NO, can be achieved through many means, including selective nNOS inhibitors, Ca2+ channel blockers [NMDA, Kainate/AMPA] [ryanodine-sensitive, IP3], calmodulin antagonists, Ca2+... 

Although the hypothesis underlying the ability of this moderate affinity open channel blocker to differentiate between phasic physiological and tonic excitotoxic pathological activation of NMDA receptors has gained relatively wide acceptance (Mealing et al. 1997 Kornhuber and Weller 1997 Parsons et al. 1999) it is still unclear how such compounds could differentiate between normal and abnormal synaptic activation of NMDA receptors. 

Carter, A. J., Bechtel, W. D., Grauert, M., Harrison, P., Merz, H., Stransky, W. Bill 277 CL is a potent and specific ion-channel blocker of the NMDA receptor-channel complex, J. Pharmacol. Exp. Ther. 1995, 275, 1382-1389. 

Lipton S. A. (1993). Prospects for clinically tolerated NMDA antagonists open-channel blockers and alternative redox states of nitric oxide. Trends Neurosci. 16 527-532. 

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