Physicochemical and biological properties of novel amide-based steroidal inhibitors of NMDA receptors

•Synthesis 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.

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 μM, respectively) as compared with endogenous inhibitor - pregnanolone sulfate (IC50 = 24.6 μM) and pregnanolone glutamate (IC50 = 51.7 μM); (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.

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