國家衛生研究院 NHRI:Item 3990099045/14638
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    题名: Modulating the affinity and signaling bias of cannabinoid receptor 1 antagonists
    作者: Hsiao, WC;Hsin, KY;Wu, ZW;Song, JS;Yeh, YN;Chen, YF;Tsai, CH;Chen, PH;Shia, KS;Chang, CP;Hung, MS
    贡献者: Institute of Biotechnology and Pharmaceutical Research
    摘要: 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.
    日期: 2023-01
    關聯: Bioorganic Chemistry. 2023 Jan;130:Article number 106236.
    Link to: http://dx.doi.org/10.1016/j.bioorg.2022.106236
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=0045-2068&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000891084600003
    Cited Times(Scopus): https://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=85141450173
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