Memantine

Memantine is a medication used to slow the progression of moderate-to-severe Alzheimer's disease. It is believed to work by acting on NMDA receptors, working as pore blockers of these ion channels. See also Memantine.

A dysfunction of glutamatergic neurotransmission, manifested as neuronal excitotoxicity, is hypothesized to be involved in the etiology of Alzheimer's disease. Targeting the glutamatergic system, specifically NMDA receptors, offers a novel approach to treatment in view of the limited efficacy of existing drugs targeting the cholinergic system. Memantine is a low-affinity voltage-dependent uncompetitive antagonist at glutamatergic NMDA receptors. By binding to the NMDA receptor with a higher affinity than Mg2+ ions, memantine is able to inhibit the prolonged influx of Ca2+ ions, particularly from extrasynaptic receptors, which forms the basis of neuronal excitotoxicity. The low affinity, uncompetitive nature, and rapid off-rate kinetics of memantine at the level of the NMDA receptor-channel, however, preserves the function of the receptor at synapses, as it can still be activated by physiological release of glutamate following depolarization of the postsynaptic neuron.

Memantine-bound GluN1a-GluN2B NMDA receptors (7sad); GluN1a subunits are in cyan, GluN2B subunits are in green, and memantine is in magenta. Memantine binding site.