N-Methyl-d-aspartate (NMDA) subunit specific receptor antagonism has potential therapeutic application for multiple CNS pathologies. MERCK 1, MERCK 2, and MERCK 3 are novel NR2B subtype selective NMDA receptor antagonists. The affinity and the kinetic mechanism of inhibition by these antagonists and ifenprodil were investigated using the whole-cell configuration of the patch clamp technique, calcium flux, and radioligand binding on a mouse cell line L(tk-) expressing recombinant human heteromeric NMDA receptors consisting of NR1a/NR2B subunit combinations. The rank order of potency, as determined by electrophysiology, was ifenprodil < MERCK 2 < MERCK 1 < MERCK 3 with KD's 79 ± 8, 2.4 ± 1.1, 1.3 ± 0.9, and ∼0.16 ± 0.02 nM, respectively. The apparent dissociation rate constants among these compounds differed by as much as 394-fold whereas the apparent association constants varied less than 3-fold. Higher affinities were a result of slower drug dissociation kinetics of receptor unbinding. Maximal inhibition was not voltage-dependent and was not statistically different at saturating concentrations by these compounds. These results provide the first detailed functional analysis of the kinetic mechanism of MERCK 1, MERCK 2, and MERCK 3 inhibition of NMDA receptors. © 2005 Elsevier Ltd. All rights reserved.
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