Allosteric and orthosteric pharmacology of cannabidiol and cannabidiol-dimethylheptyl at the type 1 and type 2 cannabinoid receptors
| Autor: | Melanie E. M. Kelly, Mylyne Tham, Robert B. Laprairie, Eileen M. Denovan-Wright, Orhan Yilmaz, Mariam Alaverdashvili |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Pharmacology Agonist Allosteric modulator medicine.drug_class Chemistry medicine.medical_treatment Allosteric regulation digestive system Partial agonist digestive system diseases 03 medical and health sciences surgical procedures operative 030104 developmental biology 0302 clinical medicine medicine Cannabinoid receptor type 2 Inverse agonist lipids (amino acids peptides and proteins) Cannabinoid Receptor 030217 neurology & neurosurgery |
| Zdroj: | British Journal of Pharmacology. 176:1455-1469 |
| ISSN: | 0007-1188 |
| DOI: | 10.1111/bph.14440 |
| Popis: | Background and purpose We sought to understand why (-)-cannabidiol (CBD) and (-)-cannabidiol-dimethylheptyl (CBD-DMH) exhibit distinct pharmacology, despite near identical structures. Experimental approach HEK293A cells expressing either human type 1 cannabinoid (CB1 ) receptors or CB2 receptors were treated with CBD or CBD-DMH with or without the CB1 and CB2 receptor agonist CP55,940, CB1 receptor allosteric modulator Org27569 or CB2 receptor inverse agonist SR144528. Ligand binding, cAMP levels and βarrestin1 recruitment were measured. CBD and CBD-DMH binding was simulated with models of human CB1 or CB2 receptors, based on the recently published crystal structures of agonist-bound (5XRA) or antagonist-bound (5TGZ) human CB1 receptors. Key results At CB1 receptors, CBD was a negative allosteric modulator (NAM), and CBD-DMH was a mixed agonist/positive allosteric modulator. CBD and Org27569 shared multiple interacting residues in the antagonist-bound model of CB1 receptors (5TGZ) but shared a binding site with CP55,940 in the agonist-bound model of CB1 receptors (5XRA). The binding site for CBD-DMH in the CB1 receptor models overlapped with CP55,940 and Org27569. At CB2 receptors, CBD was a partial agonist, and CBD-DMH was a positive allosteric modulator of cAMP modulation but a NAM of βarrestin1 recruitment. CBD, CP55,940 and SR144528 shared a binding site in the CB2 receptor models that was separate from CBD-DMH. Conclusion and implications The pharmacological activity of CBD and CBD-DMH in HEK293A cells and their modelled binding sites at CB1 and CB2 receptors may explain their in vivo effects and illuminates the difficulties associated with the development of allosteric modulators for CB1 and CB2 receptors. Linked articles This article is part of a themed section on 8th European Workshop on Cannabinoid Research. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.10/issuetoc. |
| Databáze: | OpenAIRE |
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