Modulating the affinity and signaling bias of cannabinoid receptor 1 antagonists.

Autor: Hsiao WC; Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 35053, Taiwan, ROC., Hsin KY; Department of Animal Science, National Chung Hsing University, Taichung 40227, Taiwan., Wu ZW; Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 35053, Taiwan, ROC., Song JS; Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 35053, Taiwan, ROC., Yeh YN; Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 35053, Taiwan, ROC., Chen YF; Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 35053, Taiwan, ROC., Tsai CH; Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 35053, Taiwan, ROC., Chen PH; Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 35053, Taiwan, ROC., Shia KS; Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 35053, Taiwan, ROC., Chang CP; Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 35053, Taiwan, ROC; Department of Chemistry, Chung Yuan Christian University, Taoyuan 320314, Taiwan. Electronic address: cpc1020@nhri.edu.tw., Hung MS; Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 35053, Taiwan, ROC. Electronic address: mhung@nhri.edu.tw.
Jazyk: angličtina
Zdroj: Bioorganic chemistry [Bioorg Chem] 2023 Jan; Vol. 130, pp. 106236. Date of Electronic Publication: 2022 Nov 04.
DOI: 10.1016/j.bioorg.2022.106236
Abstrakt: Cannabinoid receptor 1 (CB1) is a G protein-coupled receptor and a therapeutic target for metabolic disorders. Numerous CB1 antagonists have been developed, but their functional selectivities and bias towards G protein or β-arrestin signaling have not been systemically characterized. In this study, we analyzed the binding affinities and downstream signaling of two series of pyrazole derivatives bearing 1-aminopiperidine (Series I) or 4-aminothiomorpholine 1,1-dioxide (Series II) moieties, as well as the well-known CB1 antagonists rimonabant and taranabant. Analyses of the results for the Series I and II derivatives showed that minor structure modifications to their functional groups and especially the incorporation of 1-aminopiperidine or 4-aminothiomorpholine 1,1-dioxide motifs can profoundly affect their bias toward G protein or β-arrestin signaling, and that their binding affinity and functional activity can be disassociated. Docking and molecular dynamics simulations revealed that the binding modes of Series I and II antagonists differed primarily in that Series I antagonists formed an additional hydrogen bond with the receptor, whereas those in Series II formed a water bridge.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2022. Published by Elsevier Inc.)
Databáze: MEDLINE
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