Transient receptor potential (TRP) channels are a group of membrane proteins involved in the transduction of a plethora of chemical and physical stimuli. These channels modulate ion entry, mediating a variety of neural signaling processes implicated in the sensation of temperature, pressure, and pH, as well as smell, taste, vision, and pain perception. Many diseases involve TRP channel dysfunction, including neuropathic pain, inflammation, and respiratory disorders. In the pursuit of new treatments for these disorders, it was discovered that cannabinoids can modulate a certain subset of TRP channels. The TRP vanilloid (TRPV), TRP ankyrin (TRPA), and TRP melastatin (TRPM) subfamilies were all found to contain channels that can be modulated by several endogenous, phytogenic, and synthetic cannabinoids. To date, six TRP channels from the three subfamilies mentioned above have been reported to mediate cannabinoid activity: TRPV1, TRPV2, TRPV3, TRPV4, TRPA1, and TRPM8. The increasing data regarding cannabinoid interactions with these receptors has prompted some researchers to consider these TRP channels to be “ionotropic cannabinoid receptors.” Although CB1 and CB2 are considered to be the canonical cannabinoid receptors, there is significant overlap between cannabinoids and ligands of TRP receptors. The first endogenous agonist of TRPV1 to be discovered was the endocannabinoid, anandamide (AEA). Similarly, N-arachidonyl dopamine (NADA) and AEA were the first endogenous TRPM8 antagonists discovered. Additionally, Δ⁹-tetrahydrocannabinol (Δ⁹-THC), the most abundant psychotropic compound in cannabis, acts most potently at TRPV2, moderately modulates TRPV3, TRPV4, TRPA1, and TRPM8, though Δ⁹-THC is not reported to modulate TRPV1. Moreover, TRP receptors may modulate effects of synthetic cannabinoids used in research. One common research tool is WIN55,212-2, a CB1 agonist that also exerts analgesic effects by desensitizing TRPA1 and TRPV1. In this review article, we aim to provide an overview and classification of the cannabinoid ligands that have been reported to modulate TRP channels and their therapeutic potential.

The endocannabinoid system (ECS) has been shown to be of great importance in the regulation of numerous physiological and pathological processes. To date, two Class A G-protein-coupled receptors (GPCRs) have been discovered and validated as the main therapeutic targets of this system: the cannabinoid receptor type 1 (CB ₁ ), which is the most abundant neuromodulatory receptor in the brain, and the cannabinoid receptor type 2 (CB ₂ ), predominantly found in the immune system among other organs and tissues. Endogenous cannabinoid receptor ligands (endocannabinoids) and the enzymes involved in their synthesis, cell uptake, and degradation have also been identified as part of the ECS. However, its complex pharmacology suggests that other GPCRs may also play physiologically relevant roles in this therapeutically promising system. In the last years, GPCRs such as GPR18 and GPR55 have emerged as possible missing members of the cannabinoid family. This categorization still stimulates strong debate due to the lack of pharmacological tools to validate it. Because of their close phylogenetic relationship, the Class A orphan GPCRs, GPR3, GPR6, and GPR12, have also been associated with the cannabinoids. Moreover, certain endo-, phyto-, and synthetic cannabinoid ligands have displayed activity at other well-established GPCRs, including the opioid, adenosine, serotonin, and dopamine receptor families. In addition, the cannabinoid receptors have also been shown to form dimers with other GPCRs triggering cross-talk signaling under specific conditions. In this mini review, we aim to provide insight into the non-CB ₁ , non-CB ₂ cannabinoid-related GPCRs that have been reported thus far. We consider the physiological relevance of these molecular targets in modulating the ECS.

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.