Cannabinoid receptor ligands can selectively activate specific signaling pathways while ignoring others, a phenomenon called functional selectivity that could enable safer cannabinoid medicines with fewer side effects.
Read this if you want to understand the cutting-edge science behind designing cannabinoid medicines that work without causing unwanted effects.
Different cannabinoid compounds can selectively activate specific pathways at the same receptor
What the researchers found
This review examined the concept of functional selectivity (biased agonism) at cannabinoid receptors, a phenomenon where different drugs binding to the same receptor can trigger different cellular responses.
Traditionally, receptors were viewed as simple on/off switches. Functional selectivity reveals they are more like multi-channel dimmer switches: a drug can turn up one signaling pathway while leaving others unchanged or turning them down.
Chemically distinct classes of cannabinoid compounds show measurable signaling bias at CB1 and CB2 receptors, preferentially activating some pathways (like G-protein signaling) while not engaging others (like beta-arrestin recruitment). This selectivity appears to depend on both receptor structural features and ligand chemical properties.
The clinical significance is substantial: the adverse effects of conventional cannabinoid drugs (psychoactivity, tolerance, dependence) may be linked to specific signaling pathways. Designing drugs that avoid those pathways while activating therapeutic ones could produce safer cannabinoid medicines.
Why it matters
The clinical failure of several cannabinoid drugs (most notably rimonabant) was caused by engaging detrimental signaling pathways alongside therapeutic ones. Functional selectivity offers a solution: design drugs that activate only the beneficial pathways.
The numbers in context
The review covers multiple signaling pathways including Gi/o protein coupling, beta-arrestin recruitment, MAPK/ERK, and intracellular calcium signaling at both CB1 and CB2 receptors.
How the study worked
Review of known CB1 and CB2 signaling pathways, evidence for functional selectivity in response to endogenous and exogenous cannabinoid ligands, and structural features enabling pathway-selective receptor activation.
What this study cannot tell us
Much functional selectivity data comes from in vitro cell-based assays that may not fully predict in vivo pharmacology. The relationship between specific signaling pathways and clinical outcomes is not yet fully mapped. Designing functionally selective drugs remains technically challenging.
How to read the evidence
Review of established pharmacological concepts applied to cannabinoid receptors. Moderate because functional selectivity is well-documented in vitro but clinical translation is still developing.
When this study was published
Published in 2017.
The bigger picture
Functional selectivity is revolutionizing drug design across all G-protein coupled receptor targets, not just cannabinoid receptors. For cannabinoid medicine specifically, it offers the most promising path to separating therapeutic effects from psychoactive and adverse effects.
Questions still open
- Can specific signaling biases reliably predict clinical outcomes (therapeutic vs. adverse effects)? Could existing cannabinoid compounds be modified to achieve greater functional selectivity? Would biased agonists at cannabinoid receptors be less prone to tolerance development?
Common questions
What is functional selectivity?
How does this help develop better cannabinoid medicines?
Read the original research
Functional selectivity at G-protein coupled receptors: Advancing cannabinoid receptors as drug targets.
Biochemical pharmacology, 128, 1-11
Citation
Mallipeddi, Srikrishnan; Janero, David R; Zvonok, Nikolai; Makriyannis, Alexandros. (2017). Functional selectivity at G-protein coupled receptors: Advancing cannabinoid receptors as drug targets.. Biochemical pharmacology, 128, 1-11. https://doi.org/10.1016/j.bcp.2016.11.014
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