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

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 (IC 50  = 1.0 and 1.4 μM, respectively) as compared with endogenous inhibitor – pregnanolone sulfate (IC 50  = 24.6 μM) and pregnanolone glutamate (IC 50  = 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.