LAUSR

Graphical abstract Figure. No Caption available. HighlightsSynthesis of new amide‐based inhibitors of NMDA receptors.Strong inhibitors of NMDA currents.The Caco‐2 assay was used to evaluate permeability of new compounds.Compounds with minimal or no adverse hepatic effect.Amide‐based inhibitors of NMDA receptors are able to cross blood‐brain‐barrier. Abstract Herein, we report a new class of amide‐based inhibitors (1–4) of N‐methyl‐d‐aspartate receptors (NMDARs) that were prepared as analogues of pregnanolone sulfate (PAS) and pregnanolone glutamate (PAG) – the steroidal neuroprotective NMDAR inhibitors. A series of experiments were conducted to evaluate their physicochemical and biological properties: (i) the inhibitory effect of compounds 3 and 4 on NMDARs was significantly improved (IC50 = 1.0 and 1.4 &mgr;M, respectively) as compared with endogenous inhibitor – pregnanolone sulfate (IC50 = 24.6 &mgr;M) and pregnanolone glutamate (IC50 = 51.7 &mgr;M); (ii) physicochemical properties (logP and logD) were calculated; (iii) Caco‐2 assay revealed that the permeability properties of compounds 2 and 4 are comparable with pregnanolone glutamate; (iv) compounds 1–4 have minimal or no adverse hepatic effect; (v) compounds 1–4 cross blood‐brain‐barrier.