Efficacy profiling of structurally diverse cannabinoid receptor ligands across transducer-coupling assays
The full efficacy range of ligands at CB1 and CB2 (i.e., inverse agonists, neutral agonists, partial agonists, full agonists, and high-efficacy agonists) has been reported collectively across numerous laboratories and assay platforms. Canonical Gi/o and {beta}-arrestin signaling have each been suggested to shape physiological effects differently via different classes of cannabinoid ligands. These…
A diverse set of 22 cannabinoid ligands, including synthetic cannabinoid receptor agonists, Δ9-tetrahydrocannabinol analogues, endocannabinoid analogues, and antagonists/inverse agonists, were evaluated for their efficacy at both CB1 and CB2 receptors using bioluminescence resonance energy transfer assays. These assays measured Gi1 engagement and β-arrestin 2 recruitment, with response normalization to the full agonist CP55,940.
At CB1, selective cannabinoid receptor agonists and Δ9-THC analogues demonstrated high efficacy, while these high-efficacy agonists also showed strong β-arrestin 2 recruitment. Across all ligands, a consistent pattern emerged of declining agonist efficacy from CB1 to CB2. In the case of antagonists, inverse agonists were observed to suppress constitutive CB1 activity more effectively than neutral antagonists.
These normalized measurements, using CP55,940 as a reference, establish a standardized scale for evaluating the pharmacodynamics of CB1 and CB2 cannabinoid receptors.
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