BINDING OF THE ANTIRETROVIRAL DRUG, D-ASPARTATE-BETA-HYDROXAMATE ON THE NMDA RECEPTOR

D-Aspartate-beta-hydroxamate (D-A beta H) exhibits antiretroviral prop erties in vitro and in vivo. It has glutamate agonist properties at th e N-methyl-D-aspartate (NMDA) receptor in neuronal cell cultures. This study characterizes its binding properties to the NMDA receptor by me asuring its stimulating effect on N-(1-(2-thienyl)[H-3]cyclohexyl)pipe ridine ([H-3]TCP) binding to the ionic channel in rat brain membranes. D-A beta H stimulated [H-3]TCP binding in a dose-dependent manner but to a lower extent than glutamate, suggesting only partial glutamate a gonist properties. In the presence of antagonists of the different eff ector sites of the NMDA receptor the affinity of D-A beta H was compet itively decreased by CGS-19755 and 7-chlorokynurenate and unaffected b y arcaine. Among several D-A beta H analogues VHS.125 behaved as a ful l NMDA agonist, but L- or D-glutamate gamma-monohydroxamate (D-GH or L -GH) were without effect. This study shows that D-A beta H has potenti al neurotoxic effects due to its direct interaction with the NMDA rece ptor and that analogues such as D-GH or L-GH may rather be used in hum ans.