Modulating the affinity and signaling bias of cannabinoid receptor 1 antagonists
Copyright © 2022. Published by Elsevier Inc..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:130 |
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| Enthalten in: |
Bioorganic chemistry - 130(2023) vom: 15. Jan., Seite 106236 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Hsiao, Wen-Chi [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 29.11.2022 Date Revised 01.12.2022 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.bioorg.2022.106236 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 520 | |a 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 | ||
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| 700 | 1 | |a Yeh, Yen-Nan |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Yan-Fu |e verfasserin |4 aut | |
| 700 | 1 | |a Tsai, Chia-Hua |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Pei-Hsuan |e verfasserin |4 aut | |
| 700 | 1 | |a Shia, Kak-Shan |e verfasserin |4 aut | |
| 700 | 1 | |a Chang, Chun-Ping |e verfasserin |4 aut | |
| 700 | 1 | |a Hung, Ming-Shiu |e verfasserin |4 aut | |
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