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Signalling profiles of a structurally diverse panel of synthetic cannabinoid receptor agonists.

Authors
  • Patel, Monica1
  • Manning, Jamie J2
  • Finlay, David B2
  • Javitch, Jonathan A3
  • Banister, Samuel D4
  • Grimsey, Natasha L5
  • Glass, Michelle6
  • 1 Department of Pharmacology and Toxicology, University of Otago, Dunedin, New Zealand; Department of Pharmacology and Clinical Pharmacology, University of Auckland, Auckland, New Zealand. , (New Zealand)
  • 2 Department of Pharmacology and Toxicology, University of Otago, Dunedin, New Zealand. , (New Zealand)
  • 3 Department of Psychiatry and Pharmacology, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, United States; Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, NY, United States. , (United States)
  • 4 Lambert Initiative for Cannabinoid Therapeutics, Brain and Mind Centre, University of Sydney, NSW, Australia; School of Chemistry, Faculty of Science, University of Sydney, NSW, Australia. , (Australia)
  • 5 Department of Pharmacology and Clinical Pharmacology, University of Auckland, Auckland, New Zealand. , (New Zealand)
  • 6 Department of Pharmacology and Toxicology, University of Otago, Dunedin, New Zealand. Electronic address: [email protected] , (New Zealand)
Type
Published Article
Journal
Biochemical pharmacology
Publisher
New York, NY : Elsevier Science Inc
Publication Date
Feb 21, 2020
Volume
175
Pages
113871–113871
Identifiers
DOI: 10.1016/j.bcp.2020.113871
PMID: 32088263
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Synthetic cannabinoid receptor agonists (SCRAs) represent the most rapidly proliferating class of "designer drugs" or "new psychoactive substances". SCRAs offer unregulated alternatives to cannabis that evade routine drug tests, but their use is increasingly associated with severe toxicity and death worldwide. Little is currently known about SCRA molecular pharmacology, or the mechanisms underpinning their toxicity, although the effects are believed to be primarily mediated by the type 1 cannabinoid receptor (CB1). In this study, we aimed to characterise the signalling profiles of a structurally diverse panel of novel SCRAs at CB1. We compare SCRAs to traditional reference cannabinoids CP55,940, WIN55,212-2, and THC. The activity of the SCRAs was assessed in key receptor signalling and regulatory pathways, including cAMP production, translocation of β-arrestin 1 and 2, and receptor internalisation. The activity profiles of the ligands were also evaluated using operational analysis to identify ligand bias. Results revealed that SCRAs activities were relatively balanced in the pathways evaluated (compared to WIN55,212-2), although 5F-CUMYL-P7AICA and XLR-11 possessed partial efficacy in cAMP stimulation and β-arrestin translocation. Notably, the SCRAs showed distinct potency and efficacy profiles compared to THC. In particular, while the majority of SCRAs demonstrated robust β-arrestin translocation, cAMP stimulation, and internalisation, THC failed to elicit high efficacy responses in any of these assays. Further study is required to delineate if these pathways could contribute to SCRA toxicity in humans. Crown Copyright © 2020. Published by Elsevier Inc. All rights reserved.

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