NMDA Receptor Subtype Selective Modualtors as Alzheimer's Disease Therapeutics

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is a devastating neurodegenerative disorder. One of the few drugs used to treat AD is memantine, which inhibits N-methyl-d-aspartate receptors (NMDARs), glutamate receptor subtypes found at nearly all vertebrate excitatory synapses. NMDARs are critically involved in many aspects of nervous system function, including learning and memory. Memantine inhibits NMDARs by blocking the ion channel created by NMDARs and occluding current flow through thechannel. It is surprising that inhibition of NMDARs slows the cognitive decline associated with AD, since NMDARs are required for memory acquisition. We have proposed that memantine's utility in treating AD derives from the preferential inhibition of specific NMDAR subtypes by memantine. These NMDAR subtypes are thought to be preferentially expressed by inhibitory neurons in the cortex; as a result, memantine reduces cortical inhibition, partially compensating for a reduction in cortical excitation caused b