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 (IC₅₀=1.0 and 1.4μM, respectively) as compared with endogenous inhibitor - pregnanolone sulfate (IC₅₀=24.6μM) and pregnanolone glutamate (IC₅₀=51.7μM); (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.

Keywords: Amide; Blood-brain-barrier permeability; Caco-2 assay; NMDA receptor; Neurosteroid; Structure-activity relationship.