Binding of the antiretroviral drug, d-aspartate-β-hydroxamate on the NMDA receptor.

d-Aspartate-β-hydroxamate (d-A β H) exhibits antiretroviral properties in vitro and in vivo. It has glutamate agonist properties at the N-methyl-d-aspartate (NMDA) receptor in neuronal cell cultures. This study characterizes its binding properties to the NMDA receptor by measuring its stimulating effect on N-(1-(2-thienyl)[(3)H]cyclohexyl)piperidine ([(3)H]TCP) binding to the ionic channel in rat brain membranes. d-A β H stimulated [(3)H]TCP binding in a dose-dependent manner but to a lower extent than glutamate, suggesting only partial glutamate agonist properties. In the presence of antagonists of the different effector sites of the NMDA receptor the affinity of d-A β H was competitively decreased by CGS-19755 and 7-chlorokynurenate and unaffected by arcaine. Among several d-A β H analogues VHS.125 behaved as a full NMDA agonist, but l- or d-glutamate γ-monohydroxamate (d-GH or l-GH) were without effect. This study shows that d-A β H has potential neurotoxic effects due to its direct interaction with the NMDA receptor and that analogues such as d-GH or l-GH may rather be used in humans.