Trends in Pharmacological Sciences
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Developing the Cannabinoid Receptor 2 (CB2) pharmacopoeia: past, present, and future

  • Zak M. Whiting
    Department of Pharmacology and Clinical Pharmacology, School of Medical Sciences, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand

    Centre for Brain Research, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
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  • Jiazhen Yin
    Department of Chemistry, Division of Sciences, University of Otago, Dunedin, New Zealand
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  • Sara M. de la Harpe
    Department of Chemistry, Division of Sciences, University of Otago, Dunedin, New Zealand
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  • Andrea J. Vernall
    Department of Chemistry, Division of Sciences, University of Otago, Dunedin, New Zealand

    Maurice Wilkins Centre for Molecular Biodiscovery, Auckland, New Zealand
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  • Natasha L. Grimsey
    Department of Pharmacology and Clinical Pharmacology, School of Medical Sciences, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand

    Centre for Brain Research, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand

    Maurice Wilkins Centre for Molecular Biodiscovery, Auckland, New Zealand
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      • Cannabinoid Receptor 2 (CB2) is a promising therapeutic target, particularly for inflammatory disorders and pain; however, clinical trials to date have been unsuccessful.
      • Medicinal chemistry efforts have produced selective ligands with a wide range of core scaffolds. Optimisation for drug-like properties and oral administration has been demonstrated to be feasible, but few such compounds have been tested clinically to date.
      • Recent crystal and cryo-EM structures are expected to facilitate rational ligand development and further optimisation.
      • Although CB2 ligands can produce functional selectivity (bias) of signalling responses, few new classes of ligand have been studied in this context. The physiological relevance of CB2 signalling bias, and subcellular spatial organisation of CB2 signalling, remain to be elucidated.
      Cannabinoid Receptor 2 (CB2) is a G protein-coupled receptor (GPCR) with considerable, though as yet unrealised, therapeutic potential. Promising preclinical data supports the applicability of CB2 activation in autoimmune and inflammatory diseases, pain, neurodegeneration, and osteoporosis. A diverse pharmacopoeia of cannabinoid ligands is available, which has led to considerable advancements in the understanding of CB2 function and extensive preclinical evaluation. However, until recently, most CB2 ligands were highly lipophilic and as such not optimal for clinical application due to unfavourable physicochemical properties. A number of strategies have been applied to develop CB2 ligands to achieve closer to ‘drug-like’ properties and a few such compounds have now undergone clinical trial. We review the current state of CB2 ligand development and progress in optimising physicochemical properties, understanding advanced molecular pharmacology such as functional selectivity, and clinical evaluation of CB2-targeting compounds.


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      the strength of interaction between a ligand and receptor, typically quantified as the concentration of ligand that results in 50% of receptors binding ligand at equilibrium (Kd or Ki). A lesser concentration required to achieve 50% receptor binding indicates a higher affinity. Reported in this review via the parameter pKi.
      a receptor ligand that, upon interaction with a receptor, induces activation of one or more signalling pathways.
      Allosteric modulator
      a ligand that binds to a receptor elsewhere than the orthosteric binding site and, therefore, does not compete for binding with orthosteric ligands. By influencing receptor conformation, allosteric modulators may induce or restrict receptor activity alone or, more commonly, may positively or negatively influence the binding and/or activity of orthosteric ligands.
      a receptor ligand that binds to the orthosteric binding site (and can therefore compete for binding with other orthosteric ligands) but does not itself influence receptor activity.
      Functional selectivity
      also known as biased agonism. The concept that a single receptor type can activate varying signalling patterns (may include different pathways or the same pathways to different degrees), depending on the specific ligand bound. This is produced via the stabilisation of different receptor conformations and, therefore, differential engagement with signalling effectors.
      Inverse agonist
      a receptor ligand that reduces constitutive (non-ligand-induced) activity of a receptor by stabilising an inactive conformation.
      molecule that has affinity for a receptor.
      tendency to combine with or dissolve in nonpolar substances such as lipids. Can be measured via logD, logP.
      partition coefficient between aqueous and organic phases at a defined pH; a measure of lipophilicity. ‘c’ for calculated.
      partition coefficient between aqueous and organic phase of a neutral compound; a measure of lipophilicity. ‘c’ for calculated.
      Orthosteric binding site
      the region in a receptor where the endogenous ligand binds. Orthosteric ligands also bind to (or have overlapping interactions with) this site/pocket and can compete for binding with endogenous ligand(s).
      a parameter for quantifying ligand affinity. The negative log concentration of ligand that results in 50% of receptors binding ligand at equilibrium. A larger pKi indicates higher affinity. For example, a pKi of 9 is equal to a Ki of 1 nM, or 10–9 M. A pKi of 6 is equal to a Ki of 1 μM, or 10–6 M.
      the relative propensity of a compound to interact with and/or produce activity via one effector (e.g., a receptor) as opposed to others. Represented in this review as the fold-difference in binding affinity between two effectors. For example, a CB2/CB1 selectivity of 1000 indicates that the concentration of ligand required to bind 50% of CB1 receptors is 1000 times greater than the same for CB2.
      Target engagement
      the ability of a molecule to interact with its intended target. Encompasses molecular interactions with the target (e.g., affinity) and access to the target in vivo (e.g., drug distribution).
      Toggle switch
      in the context of GPCRs, refers to one type of molecular switch, where one or several amino acids play a key role in receptor activation by undergoing a conformational change and therefore mediating/driving the transition of the GPCR between conformations and/or stabilising a particular conformation.
      Topological polar surface area (TPSA)
      sum of surface areas of polar atoms in a molecule. Typically reported in Å2.