Novel NMDA-targeted Therapy for Alzheimer's Disease

Abstract Memantine, an aminoadamantane, is approved to treat moderate-to-severe Alzheimer's disease in the US and in Europe. Memantine selectively inhibits abnormally active N-methyl-D-aspartate-type glutamate receptor (NMDAR) channels, while preserving normal glutamate activity and physiological neuronal function (Lipton, 2006; Lipton, 2007a,b). Pathological NMDA receptor activity is further down-regulated by Snitrosylation of cysteine residues located on the N-terminus or extracellular domain. Taking advantage of these insights, PRI has developed a proprietary series of bifunctional antagonists, called nitromemantines, that not only preferentially bind to the open-channel state but also selectively target NO to a second modulatory site using the memantinepharmacophore as a homing motif (Wang, 2006, Wang et al. patents). Our data suggest that some of these memantine analogs have good potency, while maintaining selectivity for persistently open NMDAR channels. Most importantly, they appear to have greater n