Cannabidiol (CBD) has been traditionally used in Cannabis-based preparation, however historically it has received far less interest as a single drug than the other components of Cannabis. Currently, CBD generates considerable interest due to its beneficial neuroprotective, antiepileptic, anxiolytic, antipsychotic, and anti-inflammatory properties. Therefore, the CBD scaffold becomes of increasing interest for medicinal chemists. This review provides an overview of the chemical structure of natural and synthetic CBD derivatives including the molecular targets associated with these compounds. A clear identification of their biological targets has been shown to be still very challenging.

G protein-coupled receptors (GPCRs) exist within a landscape of interconvertible conformational states and in dynamic equilibrium between monomers and higher-order oligomers, both influenced by ligand binding. Here, we show that a homobivalent ligand formed by equal chromenopyrazole moieties as pharmacophores, connected by 14 methylene units, can modulate the dynamics of the cannabinoid CB₂ receptor (CB₂R) homodimerization by simultaneously binding both protomers of the CB₂R-CB₂R homodimer. Computational and pharmacological experiments showed that one of the ligand pharmacophores binds to the orthosteric site of one protomer, and the other pharmacophore to a membrane-oriented pocket between transmembranes 1 and 7 of the partner protomer. This results in unique pharmacological properties, including increased potency in G_i-mediated signaling and enhanced recruitment of β-arrestin. Thus, by modulating dimerization dynamics, it may be possible to fine-tune CB₂R activity, potentially leading to improved therapeutic outcomes.

Endocannabinoids activate two types of specific receptors, namely cannabinoid CB1 and CB2. Contrary to the psychotropic actions of agonists of CB1 receptors, and serious side effects of the selective antagonists of this receptor, drugs acting on CB2 receptors appear as promising drugs to combat CNS diseases. Differential localization of CB2 receptors in neural cell types and upregulation in neuroinflammation are keys to understand the therapeutic potential in inter alia diseases that imply progressive neurodegeneration. Medicinal chemistry approaches are now engaged to develop imaging tools to map receptors in the living human brain, to develop more efficacious agonists, and to investigate the possibility to develop allosteric modulators.

In 2005, the first evidence of an allosteric binding site at the CB₁R was provided by the identification of three indoles of the company Organon that were allosteric enhancers of agonist binding affinity and, functionally, allosteric inhibitors of agonist activity. Since then, structure–activity relationships of indoles as CB₁R modulators have been reported. Targeting the allosteric site on CB₁R, new families structurally based on urea and on 3-phenyltropane analogs of cocaine have been discovered as CB₁R-negative allosteric modulators (NAMs), respectively, by Prosidion and by the Research Triangle Park. Endogenous allosteric ligands of different nature have been identified more recently. Thus, the therapeutic neuroprotection application of lipoxin A4, an arachidonic acid derivative, as an allosteric enhancer of CB₁R activity has been confirmed in vivo. It was also the case of the steroid hormone, pregnenolone, whose negative allosteric effects on Δ⁹-tetrahydrocannabinol (Δ⁹-THC) were reproduced in vivo in a behavioral tetrad model and in food intake and memory impairment assays. Curiously, the peroxisome proliferator-activated receptor-γ agonist fenofibrate or polypeptides such as pepcan-12 have been shown to act on the endocannabinoid system through CB₁R allosteric modulation. The mechanistic bases of the effects of the phytocannabinoid cannabidiol (CBD) are still not fully explained. However, there is evidence that CBD behaves as an NAM of Δ⁹-THC- and 2-AG. Allosteric modulation at CB₁R offers new opportunities for therapeutic applications. Therefore, further understanding of the chemical features required for allosteric modulation as well as their orthosteric probe dependence may broaden novel approaches for fine-tuning the signaling pathways of the CB₁R.