Leveraging allostery to improve G protein-coupled receptor (GPCR)-directed therapeutics: cannabinoid receptor 1 as discovery target

ABSTRACT

Introduction: Allosteric modulators of G-protein coupled receptors (GPCRs) hold the promise of improved pharmacology and safety over typical orthosteric GPCR ligands. These features are particularly relevant to the cannabinoid receptor 1 (CB1R) GPCR, since typical orthosteric CB1R ligands are associated with adverse events that limit their translational potential.

Areas covered: The contextual basis for applying allostery to CB1R is considered from pharmacological, drug-discovery, and medicinal standpoints. Rational design of small-molecule CB1R allosteric modulators as potential pharmacotherapeutics would be greatly facilitated by direct experimental characterization of structure-function correlates underlying the biological activity of chemically-diverse CB1R allosteric modulators, CB1R allosteric ligand-binding binding pockets, and amino acid contact residues critical to allosteric ligand engagement and activity. In these regards, designer covalent probes exhibiting well-characterized molecular pharmacology as CB1R allosteric modulators are emerging as valuable molecular reporters enabling experimental interrogation of CB1R allosteric site(s) and informing the design of new CB1R agents as drugs.

Expert opinion: Synthesis and pharmacological profiling of CB1R allosteric ligands will continue to provide valuable insights into CB1R structure-function correlates. The resulting data should expand the repertoire of novel agents capable of exerting therapeutic benefit by modulating CB1R-dependent signaling.

KEYWORDS:

• Allosteric modulator
• binding motif
• cannabinoid GPCR
• chemical probe
• endocannabinoid system
• isothiocyanate
• ligand bias
• molecular pharmacology
• orthosteric modulator
• signal transduction
• transmembrane receptor

Article highlights

• An allosteric ligand binds to a G-protein coupled receptor (GPCR) site structurally and topographically distinct from the classical orthosteric site that engages endogenous ligands. Cooperative conformational and functional coupling between allosteric and orthoseteric binding pockets enables an allosteric ligand to modulate the affinity/efficacy of an orthosteric ligand and the magnitude/direction of the GPCR’s signaling output.

• Allosteric GPCR modulators display several unique properties that, if translatable into the clinic, could lead to improved, safer drugs.

• The cannabinoid receptor 1 (CB1R) is a metabotropic class-A GPCR involved in diverse physiological activities and implicated in the pathology of several disease states with major unmet medical needs.

• Despite the (pre)clinical therapeutic benefits associated with some novel orthosteric CB1R ligands, these agents have met with little translational success due to their on-target adverse events that might be circumvented with CB1R allosteric modulators.

• Improved understanding of CB1R allosteric binding pocket(s) and the requirements for allosteric-ligand recognition, engagement, and activity is critical to inform the rational design of CB1R allosteric modulators as pharmacotherapeutics.

• Covalent ligands pharmacologically active as allosteric modulators have recently been applied as designer probes to interrogate directly and experimentally the structure-function correlates of CB1R allosteric ligand-binding site(s).

• Information on the interaction profiles and molecular pharmacology of CB1R allosteric ligands will continue to inform GPCR allostery as a therapeutic modality and guide the design, targeting, and application of new-generation CB1R ligands as potential drugs.

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Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

GA Thakur was supported by National Institutes of Health grants DA027113 and EY024717.