Efficacy profiling of structurally diverse cannabinoid receptor ligands across transducer-coupling assays

Abstract

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 prior efficacy classifications, however, were obtained in multiple assay systems, often using indirect, amplified readouts and different reference agonists, making them difficult to compare across ligands. Here we profiled a structurally diverse panel of 22 cannabinoid ligands: synthetic cannabinoid receptor agonists (SCRAs), {Delta}-tetrahydrocannabinol ({Delta}-THC) analogues, endocannabinoid analogues, and antagonists/inverse agonists at CB1 and CB2 receptors using bioluminescence resonance energy transfer (BRET) assays, measuring Gi1 engagement and {beta}-arrestin 2 recruitment and normalizing every response to the reference full agonist CP55,940. At CB1, SCRAs and {Delta}-THC analogues acted as high-efficacy agonists. At CB1, these high-efficacy agonists were also highly efficacious in {beta}-arrestin 2 recruitment. Across the panel, the most consistent trend was a loss of agonist efficacy from CB1 to CB2. Among antagonists, inverse agonists suppressed constitutive CB1 activity more than neutral antagonists. Together, these CP55,940-normalized measurements provide a common efficacy scale and a framework for interpreting pharmacodynamics of CB1 and CB2 cannabinoid receptors.

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BibTeX RIS

BibTeX

@misc{oh2026efficacy,
  title = {{Efficacy profiling of structurally diverse cannabinoid receptor ligands across transducer-coupling assays}},
  author = {S. J. Oh and C. Lucaj and K. Truong and R. Guo and H. Umaoka and C. Iliopoulos-Tsoutsouvas and M. Gerasi and M.-O. Georgiadis and L. Ji and S. P. Nikas and A. Makriyannis and H. Yano},
  howpublished = {bioRxiv},
  year = {2026},
  month = sep,
  doi = {10.64898/2026.09.27.754774},
  url = {https://www.biorxiv.org/content/10.64898/2026.09.27.754774v1},
  note = {CC BY-NC-ND},
}

RIS

TY  - UNPB
TI  - Efficacy profiling of structurally diverse cannabinoid receptor ligands across transducer-coupling assays
AU  - S. J. Oh
AU  - C. Lucaj
AU  - K. Truong
AU  - R. Guo
AU  - H. Umaoka
AU  - C. Iliopoulos-Tsoutsouvas
AU  - M. Gerasi
AU  - M.-O. Georgiadis
AU  - L. Ji
AU  - S. P. Nikas
AU  - A. Makriyannis
AU  - H. Yano
PY  - 2026
DA  - 2026/09/27
PB  - bioRxiv
DO  - 10.64898/2026.09.27.754774
UR  - https://www.biorxiv.org/content/10.64898/2026.09.27.754774v1
AB  - 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 prior efficacy classifications, however, were obtained in multiple assay systems, often using indirect, amplified readouts and different reference agonists, making them difficult to compare across ligands. Here we profiled a structurally diverse panel of 22 cannabinoid ligands: synthetic cannabinoid receptor agonists (SCRAs), {Delta}-tetrahydrocannabinol ({Delta}-THC) analogues, endocannabinoid analogues, and antagonists/inverse agonists at CB1 and CB2 receptors using bioluminescence resonance energy transfer (BRET) assays, measuring Gi1 engagement and {beta}-arrestin 2 recruitment and normalizing every response to the reference full agonist CP55,940. At CB1, SCRAs and {Delta}-THC analogues acted as high-efficacy agonists. At CB1, these high-efficacy agonists were also highly efficacious in {beta}-arrestin 2 recruitment. Across the panel, the most consistent trend was a loss of agonist efficacy from CB1 to CB2. Among antagonists, inverse agonists suppressed constitutive CB1 activity more than neutral antagonists. Together, these CP55,940-normalized measurements provide a common efficacy scale and a framework for interpreting pharmacodynamics of CB1 and CB2 cannabinoid receptors.
ER  -

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