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Allosteric and orthosteric pharmacology of cannabidiol and cannabidiol-dimethylheptyl at the type 1 and type 2 cannabinoid receptors.
Br J Pharmacol. 2019 05; 176(10):1455-1469.BJ

Abstract

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.

Authors+Show Affiliations

College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, SK, Canada.College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, SK, Canada.College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, SK, Canada.Department of Pharmacology, Dalhousie University, Halifax, NS, Canada. Department of Opthamology and Visual Sciences, Dalhousie University, Halifax, NS, Canada.Department of Pharmacology, Dalhousie University, Halifax, NS, Canada.College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, SK, Canada. Department of Pharmacology, Dalhousie University, Halifax, NS, Canada.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

29981240

Citation

Tham, Mylyne, et al. "Allosteric and Orthosteric Pharmacology of Cannabidiol and Cannabidiol-dimethylheptyl at the Type 1 and Type 2 Cannabinoid Receptors." British Journal of Pharmacology, vol. 176, no. 10, 2019, pp. 1455-1469.
Tham M, Yilmaz O, Alaverdashvili M, et al. Allosteric and orthosteric pharmacology of cannabidiol and cannabidiol-dimethylheptyl at the type 1 and type 2 cannabinoid receptors. Br J Pharmacol. 2019;176(10):1455-1469.
Tham, M., Yilmaz, O., Alaverdashvili, M., Kelly, M. E. M., Denovan-Wright, E. M., & Laprairie, R. B. (2019). Allosteric and orthosteric pharmacology of cannabidiol and cannabidiol-dimethylheptyl at the type 1 and type 2 cannabinoid receptors. British Journal of Pharmacology, 176(10), 1455-1469. https://doi.org/10.1111/bph.14440
Tham M, et al. Allosteric and Orthosteric Pharmacology of Cannabidiol and Cannabidiol-dimethylheptyl at the Type 1 and Type 2 Cannabinoid Receptors. Br J Pharmacol. 2019;176(10):1455-1469. PubMed PMID: 29981240.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Allosteric and orthosteric pharmacology of cannabidiol and cannabidiol-dimethylheptyl at the type 1 and type 2 cannabinoid receptors. AU - Tham,Mylyne, AU - Yilmaz,Orhan, AU - Alaverdashvili,Mariam, AU - Kelly,Melanie E M, AU - Denovan-Wright,Eileen M, AU - Laprairie,Robert B, Y1 - 2018/08/10/ PY - 2017/11/06/received PY - 2018/06/15/revised PY - 2018/06/26/accepted PY - 2018/7/8/pubmed PY - 2020/7/22/medline PY - 2018/7/8/entrez SP - 1455 EP - 1469 JF - British journal of pharmacology JO - Br J Pharmacol VL - 176 IS - 10 N2 - 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. SN - 1476-5381 UR - https://www.unboundmedicine.com/medline/citation/29981240/Allosteric_and_orthosteric_pharmacology_of_cannabidiol_and_cannabidiol_dimethylheptyl_at_the_type_1_and_type_2_cannabinoid_receptors_ DB - PRIME DP - Unbound Medicine ER -