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- W4281736276 endingPage "680" @default.
- W4281736276 startingPage "680" @default.
- W4281736276 abstract "Kappa-opioid receptor (KOR) antagonists are promising innovative therapeutics for the treatment of the central nervous system (CNS) disorders. The new scaffold opioid ligand, Compound A, was originally found as a mu-opioid receptor (MOR) antagonist but its binding/selectivity and activation profile at the KOR and delta-opioid receptor (DOR) remain elusive. In this study, we present an in vitro, in vivo and in silico characterization of Compound A by revealing this ligand as a KOR antagonist in vitro and in vivo. In the radioligand competitive binding assay, Compound A bound at the human KOR, albeit with moderate affinity, but with increased affinity than to the human MOR and without specific binding at the human DOR, thus displaying a preferential KOR selectivity profile. Following subcutaneous administration in mice, Compound A effectively reverse the antinociceptive effects of the prototypical KOR agonist, U50,488. In silico investigations were carried out to assess the structural determinants responsible for opioid receptor subtype selectivity of Compound A. Molecular docking, molecular dynamics simulations and dynamic pharmacophore (dynophore) generation revealed differences in the stabilization of the chlorophenyl moiety of Compound A within the opioid receptor binding pockets, rationalizing the experimentally determined binding affinity values. This new chemotype bears the potential for favorable ADMET properties and holds promise for chemical optimization toward the development of potential therapeutics." @default.
- W4281736276 created "2022-06-13" @default.
- W4281736276 creator A5002057508 @default.
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- W4281736276 creator A5070857677 @default.
- W4281736276 creator A5078916398 @default.
- W4281736276 date "2022-05-28" @default.
- W4281736276 modified "2023-10-14" @default.
- W4281736276 title "In Vitro, In Vivo and In Silico Characterization of a Novel Kappa-Opioid Receptor Antagonist" @default.
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