MOLECULAR DESIGN OF THE N-METHYL-D-ASPARTATE RECEPTOR-BINDING SITE FOR PHENCYCLIDINE AND DIZOLCIPINE

The N-methyl-D-aspartate receptor (NMDAR), a pivotal entity for synapt ic plasticity and excitotoxicity in the brain, is a target of psychoto mimetic drugs such as phencyclidine (PCP) and dizolcipine (MK-801), In contrast, a related glutamate receptor, the alpha-amino-3-hydroxy-5-m ethyl-4-isoxazole propionate/kainate receptor GluR1, is weakly sensiti ve to these drugs. Three point mutations on GluR1, mimicking homologou s residues on the NMDAR, confer the PCP and MK-801 blockade properties that are characteristic of the NMDAR-namely, high potency, voltage de pendence, and use dependence, The molecular determinants that specify the PCP block appear confined to the putative M2 transmembrane segment , whereas the sensitivity to MK-801 requires an interplay between resi dues from M2 and M3. Given the plausible involvement of the NMDAR in t he etiology of several neurodegenerative diseases and in excitotoxic n euronal cell death, tailored glutamate receptors with specific propert ies may be models for designing and screening new drugs targeted to pr event glutamate-mediated neural damage.