A universal cannabinoid CB1 and CB2 receptor TR-FRET kinetic ligand-binding assay
The <i>k</i> <sub>on</sub> values for molecules binding to CB1R varied by three orders of magnitude, from the slowest (HU308) to the fastest (rimonabant). A strong correlation between <i>k</i> <sub>on</sub> and affinity was observed for compounds binding to CB1R, indicating that the association rate primarily determines their affinity for CB1R. Unlike CB1R, a stronger correlation was found between the dissociation rate constant <i>k</i> <sub>off</sub> and the affinity for CB2R, suggesting that both <i>k</i> <sub>on</sub> and <i>k</i> <sub>off</sub> dictate the overall affinity for CB2R. Exploring the kinetic parameters of cannabinoid drug candidates could help drug development programs targeting these receptors.
Authors
- Leonard Mach
- Laura H. Heitman (ORCID: https://orcid.org/0000-0002-1381-8464)
- Dmitry B. Veprintsev (ORCID: https://orcid.org/0000-0002-3583-5409)
- Jara Bouma (ORCID: https://orcid.org/0000-0002-6572-6158)
- Eline J. Koers (ORCID: https://orcid.org/0000-0002-5352-9069)
- Sergio Barrondo (ORCID: https://orcid.org/0000-0001-8159-4872)
- Wolfgang Guba (ORCID: https://orcid.org/0000-0002-3285-5957)
- David A. Sykes (ORCID: https://orcid.org/0000-0002-6606-888X)
- Joan Sallés (ORCID: https://orcid.org/0000-0001-6727-2674)
- Erick M. Carreira (ORCID: https://orcid.org/0000-0003-1472-490X)
- Miroslav Kosar (ORCID: https://orcid.org/0000-0003-0166-7571)
- Bradley L. Hoare (ORCID: https://orcid.org/0000-0002-4011-7532)
- Leire Borrega‐Román (ORCID: https://orcid.org/0000-0003-0042-4308)
- Thais Gazzi (ORCID: https://orcid.org/0000-0002-2321-6985)
- Uwe Grether (ORCID: https://orcid.org/0000-0002-3164-9270)
- Marc Nazaré (ORCID: https://orcid.org/0000-0002-1602-2330)
- Eric A. Kusznir
- Roman C. Sarott (ORCID: https://orcid.org/0000-0001-8789-6150)
- Arne C. Rufer (ORCID: https://orcid.org/0000-0001-5092-7478)
- Morgan Scott-Dennis (ORCID: https://orcid.org/0000-0002-0300-6913)
- Kacper J. Patej (ORCID: https://orcid.org/0009-0000-4000-1006)
Institutions
- Roche (Switzerland) (CH)
- University of Nottingham (GB)
- University of the Basque Country (ES)
- ETH Zurich (CH)
- Centro de Investigación Biomédica en Red de Salud Mental (ES)
- University of Birmingham (GB)
Publication Details
- Journal
- Frontiers in Pharmacology
- Published
- 2025-04-09
- DOI
- https://doi.org/10.3389/fphar.2025.1469986
- Citations
- 2
- Primary Topic
- Cannabis and Cannabinoid Research
- Type
- article
- Field-Weighted Citation Impact
- 2.79
Funders
- Medical Research Council