Glutamate-based therapeutic approaches: NR2B receptor antagonists.
Over the past decade, there have been major advances in our understanding of the role of glutamate and N-methyl-d-aspartate (NMDA) receptors in several disorders of the central nervous system, including stroke, Parkinson's disease, Huntington's disease and chronic/neuropathic pain. In particular, NR2B subunit-containing NMDA receptors have been the focus of intense study from both a physiological and a pharmacological perspective, with several pharmaceutical companies developing NR2B subtype-selective antagonists for several glutamate-mediated diseases. Recent studies have shown the importance of NR2B subunits for NMDA receptor localization and endocytosis, and have suggested a role for NR2B-containing NMDA receptors in the underlying pathophysiology of neurodegenerative disorders such as Alzheimer's and Huntington's diseases. Anatomical, biochemical and pharmacological studies over the past five years have greatly added to our understanding of the role of NR2B subunit-containing NMDA receptors in chronic and neuropathic pain states, and have shown that NR2B-mediated analgesic effects might be supra- rather than intra-spinally mediated, and that phosphorylation of the NR2B subunit could be responsible for the initiation and maintenance of the central sensitization seen in neuropathic pain states. These data will hopefully provide the impetus for development of novel compounds that use multiple approaches to modulate the activity of NR2B subunit-containing NMDA receptors, thus bringing to fruition the promise of therapeutic efficacy utilizing this approach.
Gogas
Kathleen R
KR
Neuroscience Department, Neurocrine Biosciences, 12790 El Camino Real, San Diego, CA 92129, USA. kgogas@neurocrine.com
D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy* / Q000378:metabolism; D002986:Clinical Trials as Topic; D004195:Disease Models, Animal; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D018698:Glutamic Acid / Q000378:metabolism; D006801:Humans; D006816:Huntington Disease / Q000188:drug therapy* / Q000378:metabolism; D010146:Pain / Q000188:drug therapy* / Q000378:metabolism; D010636:Phenols / Q000494:pharmacology / Q000627:therapeutic use; D010880:Piperidines / Q000494:pharmacology / Q000627:therapeutic use; D011487:Protein Conformation; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000378:metabolism
D018691:Excitatory Amino Acid Antagonists; C121001:NR2B NMDA receptor; D010636:Phenols; D010880:Piperidines; D016194:Receptors, N-Methyl-D-Aspartate; C109643:Ro 25-6981; D018698:Glutamic Acid; C095106:traxoprodil mesylate; C010739:ifenprodil