Design of Negative and Positive Allosteric Modulators of the Cannabinoid CB₂ Receptor Derived from the Natural Product Cannabidiol

Abstract

Cannabidiol (CBD), the second most abundant of the active compounds found in the Cannabis sativa plant, is of increasing interest because it is approved for human use and is neither euphorizing nor addictive. Here, we design and synthesize novel compounds taking into account that CBD is both a partial agonist, when it binds to the orthosteric site, and a negative allosteric modulator, when it binds to the allosteric site of the cannabinoid CB2 receptor. Molecular dynamic simulations and site-directed mutagenesis studies have identified the allosteric site near the receptor entrance. This knowledge has permitted to perform structure-guided design of negative and positive allosteric modulators of the CB2 receptor with potential therapeutic utility.

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

“…As would be expected from an allosteric mode of action, the binding of the compound to the allosteric site causes conformational changes in such a way that biases the effect of orthosteric agonists (Navarro et al, 2018a). A more recent report shows that structural changes in the molecule shifts negative to positive modulation (of the CB 2 R) thus confirming its allosteric nature (Navarro et al, 2021).…”

“…Thus, cannabidiol binds to an allosteric site at nanomolar concentrations while micromolar concentrations are required for significant binding to the orthosteric site. Accordingly, the in vitro results depend on the concentration while the in vivo actions at moderate doses should be mainly due to its binding to the allosteric site that has been very recently suggested to be close to the receptor entrance ( Navarro et al, 2021 ) (See section: “Structural Insights into CB 2 R Binding Modes”). As would be expected from an allosteric mode of action, the binding of the compound to the allosteric site causes conformational changes in such a way that biases the effect of orthosteric agonists ( Navarro et al, 2018a ).…”

“…This crystal structure revealed the ability of ORG27569 to target an extrahelical exosite within the inner leaflet of the lipid bilayer. Even though few CB 2 R allosteric modulators have been reported and none resolved in complex with the receptor, molecular dynamic and mutagenic studies have recently shown the potential allosteric site of CBD in CB 2 R ( Navarro et al, 2021 ). This report shows that CBD can bind to an allosteric cavity close to the receptor entrance in a transmembrane portal defined by transmembrane helices 1 and 7.…”

New Insights and Potential Therapeutic Targeting of CB2 Cannabinoid Receptors in CNS Disorders

“…As a result, inhibiting CB2Rs with the antagonist AM630 would prevent the antipsychotic effects of M4 agonists. Preclinical studies also showed that cannabidiol (CBD), another major phytocannabinoid, which is devoid of intoxicating effects, has antipsychotic properties [92][93][94][95] mediated by the activation of CB2Rs [96][97][98]. It should be pointed out that CBD is a non-intoxicating rather than a non-psychoactive constituent in the cannabis plant.…”

Targeting CB2 and TRPV1: Computational Approaches for the Identification of Dual Modulators

“…For instance, the main non-psychotropic component of Cannabis sativa, cannabidiol (CBD), is a CB2 partial agonist/TRPV1 agonist (De Petrocellis et al, 2011;Tham et al, 2018). It is worth mentioning that at CB2, CBD has been reported to act as negative allosteric modulator in the presence of orthosteric full agonists (Martínez-Pinilla et al, 2017;Navarro et al, 2021). The acidic CBD derivative, cannabidiolic acid (CBDA), and its propyl counterpart, cannabivarin (CBDV), also exhibited TRPV1 agonism while being CB2 partial agonists (De Petrocellis et al, 2011;Zagzoog et al, 2020).…”