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N-methyl-D-aspartate (NMDA) receptors play important roles in development, synaptic plasticity, learning, and memory, however, abnormal activation of NMDA receptors is thought to mediate neuronal degeneration.NMDA receptor activity can be influenced by exogenous and endogenous ligands, including neurosteroids-endogenous steroids that are synthesized and act in the central nervous system.20-oxo-5β-pregnan-3α-yl sulfate (pregnanolone sulfate;PA-S) is an endogenous neurosteroid that inhibits NMDARs and is neuroprotective.To delineate the mechanism of NMDAR inhibition by PA-S patch-clamp and imagining recordings from HEK293 cells expressing NR1/NR2B receptors and cultured rat hippocampal neurons were used.The results of our electrophysiological experiments show that kinetics of the steroid inhibition is slow and not typical for drug-receptor interaction in the aqueous solution.In addition, the recovery from inhibition was accelerated by β-and γ-cyclodextrin.Values of IC50 assessed for novel synthetic C3 analogs of PA-S differ by more than 30-fold and were positively correlated with the steroid lipophilicity.The onset of inhibition induced by C3 analogs of PA-S can range from agonist-dependent to agonist-independent.The onset and offset of cell staining by fluorescent analogs of PA-S is slower than that determined of the onset and offset of these steroids induced inhibition of current responses mediated by NMDA receptors.We conclude that steroid accumulation in plasma membrane is route, from which it accesses a site on the NMDA receptor.