Journal
STEROIDS
Volume 117, Issue -, Pages 52-61Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.steroids.2016.08.010
Keywords
Neurosteroid; NMDA receptor; Structure-activity relationship; Amide; Blood-brain-barrier permeability; Caco-2 assay
Funding
- Technology Agency of the Czech Republic [TE01020028]
- Grant Agency of the Czech Republic [303/12/1464]
- National Programme sustainability Ministry of Education [NPU I - LO1302]
- Ministry of Health of the Czech Republic [NV15-29370A]
- Czech Science Foundation [P208/12/G016]
- [RVO 67985823]
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Herein, we report a new class of amide-based inhibitors (1-4) of N-methyl-o-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 mu M respectively) as compared with endogenous ihhibitor - pregnanolone sulfate (IC50 = 24.6 mu M) and pregnanolone glutamate (IC50 = 51.7 mu 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. (C) 2016 Elsevier Inc. All rights reserved.
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