The Binding Mode to Orthosteric Sites and/or Exosites Underlies the Therapeutic Potential of Drugs Targeting Cannabinoid CB2 Receptors

Abstract

The classical terms agonists and antagonists for G protein coupled receptors (GPCRs) have often become misleading. Even the biased agonism concept does not describe all the possibilities already demonstrated for GPCRs. The cannabinoid CB2 receptor (CB2R) emerged as a promising target for a variety of diseases. Reasons for such huge potential are centered around the way drugs sit in the orthosteric and/or exosites of the receptor. On the one hand, a given drug in a specific CB2R conformation leads to a signaling cascade that differs qualitatively and/or quantitatively from that triggered by another drug. On the other hand, a given drug may lead to different signaling outputs in two different tissues (or cell contexts) in which the conformation of the receptor is affected by allosteric effects derived from interactions with other proteins or with membrane lipids. This highlights the pharmacological complexity of this receptor and the need to further unravel the binding mode of CB2R ligands in order to fine-tune signaling effects and therapeutic propositions.

Terpenes fromCannabis sativaInduce Antinociception in Mouse Chronic Neuropathic Pain via Activation of Spinal Cord Adenosine A2AReceptors

“…However, our modeling studies suggested a mechanism for the terpenes to bind and activate the A 2A R in the orthosteric binding pocket. One possibility is that the terpenes bind to a subcompartment of the orthosteric site that permits orthosteric activation but avoids radioligand competition; analogous findings have been described for cannabinoids that compete with 3 H-WIN55,212 but not 3 H-CP55,940 at the CB1R (discussed in [54]). Another possibility is that our terpenes bind the orthosteric site in a competing pose with 3 H-ZM241385 but have unfavorable pharmacodynamic features (affinity, K ON/OFF , etc.)…”

Novel Cannabinoid Receptor 2 (CB2) Low Lipophilicity Agonists Produce Distinct cAMP and Arrestin Signalling Kinetics without Bias

“…Therefore, if an allosteric mechanism is contributing to the kinetic signalling profiles observed, the ligands might be acting “dualsterically” with an allosteric site in close spatial proximity to the orthosteric site, have transient allosteric interactions, or be acting via dual binding at the orthosteric site and a distant allosteric site on the same or dimerised receptor protomer [ 34 , 35 , 36 , 37 ]. Various allosteric sites in CB2 have been predicted, including at least one near the orthosteric site [ 31 , 38 , 39 , 40 , 41 ]. Interestingly, all the test compounds we studied had a considerably higher signalling potency:affinity ratio than CP55,940, which could also indicate involvement of an allosteric mechanism in the transduction of signalling for the test compounds [ 37 ].…”

Potential of CBD Acting on Cannabinoid Receptors CB1 and CB2 in Ischemic Stroke

“…When these ligands interact with the CB 2 receptor, they can modulate its function, leading to a range of potential therapeutic benefits [ 48 ]. For instance, cannabidiol acts as a negative allosteric modulator of CB 2 R, inducing conformational changes in such a way that biases the effect of orthosteric agonists [ 49 ].…”