NMDA receptors therapeutic potential

Leeson PD, Iversen LL (1994) The glycine site on the NMDA receptor structure-activity relationships and therapeutic potential. J Med Chem 37(24) 4053-4067... 

Interest in the therapeutic potential of drugs acting on the NMDA receptor has risen with the discovery that epilepsy and related convulsive states may occur as a consequence of a sudden release of glutamate. Sustained seizures of the limbic system in animals result in brain damage that resembles the changes seen in glutamate toxicity. Similar changes are... 

Laboratory studies have identified numerous glutamatergic targets for potential therapeutic interventions in TBI (Bullock et al. 1999). Of these potential therapies, only NMDA receptor antagonists have progressed into human clinical trials, but, as stated above, most of these trials were terminated prematurely. 

The PA4 peptide and an excessive amount of APP have proved to be neurotoxic. The accumulation of the pA4 peptide between synapses may be responsible for neuronal dysfunction and death (Schubert et al. 1991). PA4 could also modify the N-methyl-D-aspartate (NMDA) receptor, making possible the presence of neurotoxicity via the excitotoxin and calcium pathways [Mattson et al. 1992). Drugs that interfere with these pathways or alter calcium homeostasis have a potential therapeutic role. 

A bioxantracene (-)-ES-242-4 (46) was isolated from the culture broth of Verticillium sp. in 1992 as one of eight antagonists for the 7V-methy 1-D-aspartate (NMDA) receptor (7<5). These novel natural products are reported to inhibit the PH]thienyl cyclohexylpiperidine binding to rat crude synaptic membranes, and therefore, are of potential therapeutic interest for die treatment of neurodegenerative diseases. (-)-ES-242-4 (46) is structurally remarkable having an axially chiral binaphthalene core that is adorned with two pyrans of the same absolute chirality. Our interest in the construction of densely functionalized naphthopyran ring systems, via tandem Michael-Dieckmann reactions, promoted us to attempt the first stereocontrolled total synthesis of (-)-ES-242-4 (46) (19). 

As described in section 2.3, metabotropic receptors are divided into families, based upon second messenger mechanisms and functional effect. Group I receptors potentiate presynaptic glutamate release and NMDA receptor-mediated neurotransmission. Therapeutic effectiveness of group I agonists is therefore... 

Alongside these largely electrophysiological studies, others showed that NMDA receptors mediated profound neurotoxicity [26-30] and have a central role in epileptiform discharges [31-32] in vitro and in vivo. As a result, the therapeutic potential of NMDA receptor antagonists has emerged and several agents are under development by pharmaceutical companies [33]. 

Cai SX (2006) Glycine/NMDA receptor antagonists as potential CNS therapeutic agents ACEA-1021 and related compounds. Curr Top Med Chem 6 651-662... 

Mony L, Kew JN, Gunthorpe MJ et al (2009) Allosteric modulators of NR2B-containing NMDA receptors molecular mechanisms and therapeutic potential. Br J Pharmacol 157 1301-1317... 

This section will deal with the major potential therapeutic applications of agonists and antagonists acting on glutamate receptors. Potential applications are listed in Table 2 together with the approaches being proposed. Evidences for some indications are stronger than others and, as mentioned above, this part of the review will mainly concentrate on the NMDA receptor as this is the receptor that has been studied the most. Where there are clear indications for other receptor types they will be discussed. 

Conantokins bind to the V-methyl-D-aspartate (NMDA) receptor, one form of ionotropic glutamate receptor. The therapeutic potential of clinically available NMDA receptor antagonists is currently limited because of the prevalence of undesirable side effects, thought to be a result of a lack of specificity. 

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