The Binding Mode to Orthosteric Sites and/or Exosites Underlies the Therapeutic Potential of Drugs Targeting Cannabinoid CB2 Receptors
The classical terms agonists and antagonists for G protein coupled receptors (GPCRs) have often become misleading. Even the biased agonism concept does not describe all the possibilities already demonstrated for GPCRs. The cannabinoid CB2 receptor (CB2R) emerged as a promising target for a variety o...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-02-01
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| Series: | Frontiers in Pharmacology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2022.852631/full |
| _version_ | 1819277281279868928 |
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| author | Rafael Franco Rafael Franco Rafael Franco Paula Morales Gemma Navarro Gemma Navarro Nadine Jagerovic Irene Reyes-Resina Irene Reyes-Resina |
| author_facet | Rafael Franco Rafael Franco Rafael Franco Paula Morales Gemma Navarro Gemma Navarro Nadine Jagerovic Irene Reyes-Resina Irene Reyes-Resina |
| author_sort | Rafael Franco |
| collection | DOAJ |
| description | The classical terms agonists and antagonists for G protein coupled receptors (GPCRs) have often become misleading. Even the biased agonism concept does not describe all the possibilities already demonstrated for GPCRs. The cannabinoid CB2 receptor (CB2R) emerged as a promising target for a variety of diseases. Reasons for such huge potential are centered around the way drugs sit in the orthosteric and/or exosites of the receptor. On the one hand, a given drug in a specific CB2R conformation leads to a signaling cascade that differs qualitatively and/or quantitatively from that triggered by another drug. On the other hand, a given drug may lead to different signaling outputs in two different tissues (or cell contexts) in which the conformation of the receptor is affected by allosteric effects derived from interactions with other proteins or with membrane lipids. This highlights the pharmacological complexity of this receptor and the need to further unravel the binding mode of CB2R ligands in order to fine-tune signaling effects and therapeutic propositions. |
| first_indexed | 2024-12-23T23:53:37Z |
| format | Article |
| id | doaj.art-afbbc5a71e5e4873b7b89ddbc373f385 |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-12-23T23:53:37Z |
| publishDate | 2022-02-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-afbbc5a71e5e4873b7b89ddbc373f3852022-12-21T17:25:19ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122022-02-011310.3389/fphar.2022.852631852631The Binding Mode to Orthosteric Sites and/or Exosites Underlies the Therapeutic Potential of Drugs Targeting Cannabinoid CB2 ReceptorsRafael Franco0Rafael Franco1Rafael Franco2Paula Morales3Gemma Navarro4Gemma Navarro5Nadine Jagerovic6Irene Reyes-Resina7Irene Reyes-Resina8CiberNed. Network Center for Neurodegenerative Diseases, National Spanish Health Institute Carlos III, Madrid, SpainMolecular Neurobiology Laboratory, Department of Biochemistry and Molecular Biolomedicine, Universitat de Barcelona, Barcelona, SpainSchool of Chemistry, Universitat de Barcelona, Barcelona, SpainMedicinal Chemistry Institute, Spanish National Research Council, Madrid, SpainCiberNed. Network Center for Neurodegenerative Diseases, National Spanish Health Institute Carlos III, Madrid, SpainDepartment of Biochemistry and Physiology, Faculty of Pharmacy and Food Science, Universitat de Barcelona, Barcelona, SpainMedicinal Chemistry Institute, Spanish National Research Council, Madrid, SpainCiberNed. Network Center for Neurodegenerative Diseases, National Spanish Health Institute Carlos III, Madrid, SpainMolecular Neurobiology Laboratory, Department of Biochemistry and Molecular Biolomedicine, Universitat de Barcelona, Barcelona, SpainThe classical terms agonists and antagonists for G protein coupled receptors (GPCRs) have often become misleading. Even the biased agonism concept does not describe all the possibilities already demonstrated for GPCRs. The cannabinoid CB2 receptor (CB2R) emerged as a promising target for a variety of diseases. Reasons for such huge potential are centered around the way drugs sit in the orthosteric and/or exosites of the receptor. On the one hand, a given drug in a specific CB2R conformation leads to a signaling cascade that differs qualitatively and/or quantitatively from that triggered by another drug. On the other hand, a given drug may lead to different signaling outputs in two different tissues (or cell contexts) in which the conformation of the receptor is affected by allosteric effects derived from interactions with other proteins or with membrane lipids. This highlights the pharmacological complexity of this receptor and the need to further unravel the binding mode of CB2R ligands in order to fine-tune signaling effects and therapeutic propositions.https://www.frontiersin.org/articles/10.3389/fphar.2022.852631/fullbiased agonismheteromerhealth benefitstherapyfunctional selectivitycannabinoid receptor |
| spellingShingle | Rafael Franco Rafael Franco Rafael Franco Paula Morales Gemma Navarro Gemma Navarro Nadine Jagerovic Irene Reyes-Resina Irene Reyes-Resina The Binding Mode to Orthosteric Sites and/or Exosites Underlies the Therapeutic Potential of Drugs Targeting Cannabinoid CB2 Receptors Frontiers in Pharmacology biased agonism heteromer health benefits therapy functional selectivity cannabinoid receptor |
| title | The Binding Mode to Orthosteric Sites and/or Exosites Underlies the Therapeutic Potential of Drugs Targeting Cannabinoid CB2 Receptors |
| title_full | The Binding Mode to Orthosteric Sites and/or Exosites Underlies the Therapeutic Potential of Drugs Targeting Cannabinoid CB2 Receptors |
| title_fullStr | The Binding Mode to Orthosteric Sites and/or Exosites Underlies the Therapeutic Potential of Drugs Targeting Cannabinoid CB2 Receptors |
| title_full_unstemmed | The Binding Mode to Orthosteric Sites and/or Exosites Underlies the Therapeutic Potential of Drugs Targeting Cannabinoid CB2 Receptors |
| title_short | The Binding Mode to Orthosteric Sites and/or Exosites Underlies the Therapeutic Potential of Drugs Targeting Cannabinoid CB2 Receptors |
| title_sort | binding mode to orthosteric sites and or exosites underlies the therapeutic potential of drugs targeting cannabinoid cb2 receptors |
| topic | biased agonism heteromer health benefits therapy functional selectivity cannabinoid receptor |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2022.852631/full |
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