Memantine is a clinically well tolerated N-methyl-D-aspartate (NMDA) receptor antagonist - a review of preclinical data

N-methyl-D-aspartate (NMDA) receptor antagonists have therapeutic potential in numerous CNS disorders ranging from acute neurodegeneration (e.g. strok e and trauma), chronic neurodegeneration (e.g. Parkinson's disease, Alzheim er's disease, Huntington's disease, ALS) to symptomatic treatment (e.g. epi lepsy, Parkinson's disease, drug dependence, depression, anxiety and chroni c pain). However, many NMDA receptor antagonists also produce highly undesi rable side effects at doses within their putative therapeutic range. This h as unfortunately led to the conclusion that NMDA receptor antagonism is not a valid therapeutic approach. However, memantine is clearly an uncompetiti ve NMDA receptor antagonist at therapeutic concentrations achieved in the t reatment of dementia and is essentially devoid of such side effects at dose s within the therapeutic range. This has been attributed to memantine's mod erate potency and associated rapid, strongly voltage-dependent blocking kin etics. The aim of this review is to summarise preclinical data on memantine supporting its mechanism of action and promising profile in animal models of chronic neurodegenerative diseases. The ultimate purpose is to provide e vidence that it is indeed possible to develop clinically well tolerated NMD A receptor antagonists, a fact reflected in the recent interest of several pharmaceutical companies in developing compounds with similar properties to memantine. (C) 1999 Elsevier Science Ltd. All rights reserved.