Measured, borrowed, and unresolved: the target profile of memantine

Abstract

Memantine is used to treat Alzheimer's disease and to probe N-methyl-D-aspartate (NMDA) receptor function. Its label as an NMDA antagonist does not establish which receptor accounts for a clinical or experimental effect. Misassigning that target can turn a drug's success or failure into misleading evidence about a disease mechanism. We reanalysed published measurements of memantine inhibition at NMDA and α7 nicotinic acetylcholine receptors, combining exposure estimates, reported uncertainty and explicit modelling assumptions. At 0.25 µM, a concentration informed by human cerebrospinal fluid, the predicted target preference reversed with the source chosen: before magnesium adjustment, a native-neuron study predicted 13.3-fold greater α7 inhibition, whereas estimates from oocyte studies predicted 10.8–13.1-fold greater NMDA inhibition. Applying published magnesium shifts reduced predicted NMDA inhibition by amounts that differed across receptor subtypes. The comparison remained conditional on the source preparations, voltage and activation protocols. These measurements cannot establish which target chiefly mediates memantine's clinical benefit. They show that choosing among published potencies can reverse the mechanistic interpretation of the same exposure. Experiments and trials using memantine therefore need evidence of target inhibition at the exposure achieved before their outcomes can support or reject a receptor-specific hypothesis.