Physicochemical and biological properties of novel amide-based steroidal inhibitors of NMDA receptors
Language English Country United States Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
27544449
DOI
10.1016/j.steroids.2016.08.010
PII: S0039-128X(16)30106-4
Knihovny.cz E-resources
- Keywords
- Amide, Blood-brain-barrier permeability, Caco-2 assay, NMDA receptor, Neurosteroid, Structure-activity relationship,
- MeSH
- Amides MeSH
- Hep G2 Cells MeSH
- Caco-2 Cells MeSH
- Blood-Brain Barrier drug effects metabolism MeSH
- Humans MeSH
- Magnetic Resonance Spectroscopy MeSH
- Molecular Structure MeSH
- Neurotransmitter Agents chemistry pharmacology MeSH
- Reactive Oxygen Species metabolism MeSH
- Receptors, N-Methyl-D-Aspartate antagonists & inhibitors metabolism MeSH
- Structure-Activity Relationship MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Amides MeSH
- Neurotransmitter Agents MeSH
- Reactive Oxygen Species MeSH
- Receptors, N-Methyl-D-Aspartate MeSH
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.
References provided by Crossref.org
Palmitoylation Controls NMDA Receptor Function and Steroid Sensitivity
