|
In 1972 a possible therapeutic importance of memantine, an adamantane derivative, was discovered for treating neurodegenerative disorders. Since 1989 memantine has been recognized to be an uncompetitive antagonist of the N-methyl-D-aspartate receptor (NMDA receptor), entering the channel of the receptor after it’s been activated and thereby blocking the flow of ions.〔Johnson, J.W. & Kotermanski, S.E. (2006). Mechanism of action of memantine. Current Opinion in Pharmacology, 6(1), 61-67.〕〔Dominguez, E., Chin, T.-Y., Chen, C.-P., & Wu, T.-Y. (2011). Management of moderate to severe Alzheimer’s disease: Focus on memantine. Taiwanese Journal of Obstetrics and Gynecology, 50(4), 415-423. doi:http://dx.doi.org/10.1016/j.tjog.2011.10.004〕〔Chen, H.-S. V. & Lipton, S. A. (2006), The chemical biology of clinically tolerated NMDA receptor antagonists. Journal of Neurochemistry, 97: 1611–1626. doi: 10.1111/j.1471-4159.2006.03991.x〕 The NMDA receptor channels play an important role in synaptic plasticity and synapse formation underlying memory, learning and formation of neural networks during development in the central nervous system (CNS). Overactivation of the receptor, causing excessive influx of Ca2+ can lead to excitotoxicity which is implied to be involved in some neurodegenerative disorders. Blocking of NMDA receptors could therefore, in theory, be useful in treating such diseases.〔〔Kemp, J. A., & McKernan, R. M. (2002). NMDA receptor pathways as drug targets. Nature Neuroscience, 5(11), 1039-1042.〕〔Lipton, S.A. (2006). Paradigm shift in neuroprotection by NMDA receptor blockade: Memantine and beyond. Nature Reviews Drug Discovery, 5(2), 160-170.〕〔Koch, H.J., Szecsey, A. & Haen, E. (2004). NMDA-antagonism (Memantine): An alternative pharmacological therapeutic principle in Alzheimer’s and vascular dementia. Current Pharmaceutical Design, 10, 253-259. doi:http://dx.doi.org/10.2174/1381612043386392〕 The main problem with the development of NMDA receptor antagonist for neuroprotection is that the physiological NMDA receptor activity is essential for normal neuronal function. To be clinically accepted the antagonists must block excessive activation without blocking the normal function.〔Lipton, S. A. (2004). Failures and successes of NMDA receptor antagonists: Molecular basis for the use of open-channel blockers like memantine in the treatment of acute and chronic neurologic insults. NeuroRx, 1(1), 101-110. doi:http://dx.doi.org/10.1602/neurorx.1.1.101〕 == History == The discovery of NMDA receptors was followed by the synthesis and study of N-Methyl-D-aspartic acid (NMDA) in 1960s by Jeff Watkins and colleagues. In the early 1980s, NMDA receptors were shown to be involved in several central synaptic pathways.〔Yamakura, T., & Shimoji, K. (1999). Subunit- and site-specific pharmacology of the NMDA receptor channel. Progress in Neurobiology, 59(3), 279-298. doi: http://dx.doi.org/10.1016/S0301-0082(99)00007-6;〕〔Watkins, Jeffrey C., & Jane, David E. (2006). The glutamate story. British Journal of Pharmacology, 147(S1), S100-S108. doi: 10.1038/sj.bjp.0706444〕 Receptor subunit selectivity was discovered in the early 1990s, which led to recognition of a new class of compounds that selectively inhibit the NR2B subunit. These findings led to vigorous campaign in the pharmaceutical industry.〔Paoletti, Pierre, & Neyton, Jacques. (2007). NMDA receptor subunits: function and pharmacology. Current Opinion in Pharmacology, 7(1), 39-47. doi: http://dx.doi.org/10.1016/j.coph.2006.08.011〕 From this it was considered that NMDA receptors were associated with a variety of neurological disorders such as epilepsy, Parkinson´s, Alzheimer´s, Huntington´s and other CNS disorders.〔Dingledine, Raymond, Borges, Karin, Bowie, Derek, & Traynelis, Stephen F. (1999). The Glutamate Receptor Ion Channels. Pharmacological Reviews, 51(1), 7-62.〕 A fortuitous finding was made in 1968 when a woman was taking amantadine as flu medicine and experienced remarkable remission of her Parkinson's symptoms. This finding, reported by Scawab et al., was the beginning of medicinal chemistry of adamantane derivatives in the context of diseases affecting the CNS.〔Wanka, Lukas, Iqbal, Khalid, & Schreiner, Peter R. (2013). The Lipophilic Bullet Hits the Targets: Medicinal Chemistry of Adamantane Derivatives. Chemical Reviews, 113(5), 3516-3604. doi: 10.1021/cr100264t〕 Before this finding, memantine, another adamantane derivative, had been synthesized by Eli Lilly and Company in 1963. The purpose was to develop hypoglycemic drug, but it showed no such efficacy. It was not until 1972 that a possible therapeutic importance of memantine for treating neurodegenerative disorders was discovered. From 1989 memantine has been recognized to be an uncompetitive antagonist of the NMDA receptor.〔 抄文引用元・出典: フリー百科事典『 ウィキペディア（Wikipedia）』 ■ウィキペディアで「Discovery and development of memantine and related compounds」の詳細全文を読む スポンサード リンク
|