Development of clinically-tolerated NMDA receptor antagonists

The clinical potential of most N-methyl-D-Aspartate (NMDA) receptor antagonists as neuroprotectants is hampered by the fact that they block physiological NMDA receptor mediated activity at neuroprotective concentrations. However, unlike other NMDA antagonists, the open-channel blocker memantine displays relative sparing of excitatory postsynaptic currents (epsc) at neuroprotective levels, apparently due to its purely uncompetitive mode of antagonism. In contrast, the failure of MK-801 to spare epscs suggests that the clinical potential of an open-channel blocker is determined by its on- and off- rate constants. Is there a set of unique on- and off- rate constants that optimizes the mutually conflicting demands of neuroprotection and clinical tolerance? Using kinetic theory and exploiting the differences in temporal profile of glutamate concentrations under physiological and pathological conditions, we calculated optimal rate constants. The calculations were subject to the following three constraints: the antagonist should (i) block sustained NMDA receptor activity as much as possible, (ii) attain steady-state blockade within a reasonable time (seconds), and (iii) spare NMDA epscs to the greatest degree possible. Our calculations establish the best theoretical parameters for clinically-tolerated NMDA open-channel blockers and raise the possibility of using specific NMDA receptor channel blockers prophylactically for various neurologic disorders.