Pharmacodynamics of Memantine: An Update

Abstract

Memantine received marketing authorization from the European Agency for the Evaluation of Medicinal Products (EMEA) for the treatment of moderately severe to severe Alzheimer´s disease (AD) in Europe on 17 th May 2002 and shortly thereafter was also approved by the FDA for use in the same indication in the USA. Memantine is a moderate affinity, uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist with strong voltage-dependency and fast kinetics. Due to this mechanism of action (MOA), there is a wealth of other possible therapeutic indications for memantine and numerous preclinical data in animal models support this assumption. This review is intended to provide an update on preclinical studies on the pharmacodynamics of memantine, with an additional focus on animal models of diseases aside from the approved indication. For most studies prior to 1999, the reader is referred to a previous review [196].In general, since 1999, considerable additional preclinical evidence has accumulated supporting the use of memantine in AD (both symptomatic and neuroprotective). In addition, there has been further confirmation of the MOA of memantine as an uncompetitive NMDA receptor antagonist and essentially no data contradicting our understanding of the benign side effect profile of memantine. THERAPEUTIC TARGETThe maximal therapeutically-relevant plasma concentration of memantine is around 1 M (see [55,203]). Brain extracellular fluid (ECF) concentration of around 0.8 M can be anticipated [102] and any receptor that expresses an affinity at, or below, the very low M range should be considered as a potential therapeutic target. Given this assumption, there are only four plausible known target types to date: the most likely is the NMDA receptor channel, but 5-hydroxy-tryptamine (5-HT 3 ) receptors [220] and 7 and/or 4 2 nicotinic receptors [11] should also be taken into consideration [11,37,165].The 7 and 4 2 nicotinic acetylcholine receptor and the 5-HT 3 receptor systems have been suggested to play a role in modulating CNS functions, including learning and memory. These receptors are structurally related, containing large extracellular ligand-binding domains and four transmembrane domains that are largely conserved. They exhibit considerable cross-pharmacology, e.g. high concentrations of the 7 nAChR agonist nicotine inhibit 5-HT 3 receptor-mediated responses, and high concentrations of the 5-HT 3 receptor agonist serotonin inhibit 7 nAChR-mediated responses. Based on this knowledge, it seems reasonable to investigate whether ligands specific for either receptor, might have affinity for both. NMDA RECEPTORS Fast Kinetics and Strong Voltage-DependencyMemantine blocks the NMDA receptor channel in an use-dependent manner, meaning that it can only gain access to the channel in the presence of agonist and remains largely *Address correspondence to this author at Preclinical R & D, Merz Pharmaceuticals, Eckenheimer Landstrasse 100, 60318 Frankfurt am Main, Germany; Tel: +49 69 1503368; E-mail: christopher.parsons@m...

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