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REVIEW (Open Access)
Contents Vol 74(6)

Imaging Cannabinoid Receptors: A Brief Collection of Covalent and Fluorescent Probes for CB1 and CB2 Receptors

Alexander J. Hamilton A , Alan D. Payne B , Mauro Mocerino B and Hendra Gunosewoyo https://orcid.org/0000-0003-3897-1948 A C
+ Author Affiliations
- Author Affiliations

A Curtin Medical School, Faculty of Health Sciences, Curtin University, Perth, WA 6102, Australia.

B School of Molecular and Life Sciences, Curtin University, Perth, WA 6102, Australia.

C Corresponding author. Email: Hendra.Gunosewoyo@curtin.edu.au




Mr Alex Hamilton is a Ph.D. student studying medicinal and organic chemistry at Curtin University. His research consists of designing novel cannabinoid receptor ligands and PARP-1 inhibitors from a versatile indole scaffold, with hopes of repurposing these compounds for further diseases and infections.


Dr Alan Payne is a synthetic organic chemist at Curtin University. His main research interests are in designing new leads for drug discovery, antagonists of ethylene action in plants and fundamental hydrocarbons. Recently, he has focused on natural products from Western Australian plants as scaffolds for drug discovery.


Professor Mauro Mocerino is a teaching and research academic at Curtin University with research interest in synthetic chemistry and chemistry education. The synthetic chemistry focuses on the design and synthesis of molecules for specific intermolecular interactions including chiral recognition and drug-protein interactions, the latter focusing on anti-protozoans or human papillomavirus inhibitors. The educational research is currently exploring the potential of virtual reality for visualisation of chemical processes.


Dr Hendra Gunosewoyo is a synthetic medicinal chemist at Curtin University. His research is focused on the design and discovery of novel antimycobacterial molecules in collaboration with Johns Hopkins University. More recently, his research interests include medicinal chemistry of synthetic cannabimimetics and discovering other potential uses of indoleamides scaffold.

Australian Journal of Chemistry 74(6) 416-432 https://doi.org/10.1071/CH21007
Submitted: 5 January 2021  Accepted: 13 April 2021   Published: 27 May 2021

Journal Compilation © CSIRO 2021 Open Access CC BY

Abstract

There has been an expanding public interest towards the notion that modulation of the sophisticated endocannabinoid system can lead to various therapeutic benefits that are yet to be fully explored. In recent years, the drug discovery paradigm in this field has been largely based on the development of selective CB2 receptor agonists, avoiding the unwanted CB1 receptor-mediated psychoactive side effects. Mechanistically, target engagement studies are crucial for confirming the ligand–receptor interaction and the subsequent biological cascades that lead to the observed therapeutic effects. Concurrently, imaging techniques for visualisation of cannabinoid receptors are increasingly reported in the literature. Small molecule imaging tools ranging from phytocannabinoids such as tetrahydrocannabinol (THC) and cannabidiol (CBD) to the endocannabinoids as well as the purely synthetic cannabimimetics, have been explored to date with varying degrees of success. This Review will cover currently known photoactivatable, electrophilic, and fluorescent ligands for both the CB1 and CB2 receptors. Structural insights from techniques such as ligand-assisted protein structure (LAPS) and the discovery of novel allosteric modulators are significant additions for better understanding of the endocannabinoid system. There has also been a plethora of fluorescent conjugates that have been assessed for their binding to cannabinoid receptors as well as their potential for cellular imaging. More recently, bifunctional probes containing either fluorophores or electrophilic tags are becoming more prevalent in the literature. Collectively, these molecular tools are invaluable in demonstrating target engagement within the human endocannabinoid system.

Keywords: imaging agents, cannabinoids, fluorescent probes, electrophilic probes, photoaffinity labelling, synthetic cannabinoids, cannabinoid receptor, ligand-assisted protein structure.


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