Abstract
Activation of the human cannabinoid receptor type 1 ( hCB 1R) with high spatiotemporal control is useful to study processes involved in different pathologies related to nociception, metabolic alterations, and neurological disorders. To synthesize new agonist ligands for hCB 1R, we have designed different classes of photoswitchable molecules based on an indole core. The modifications made to the central core have allowed us to understand the molecular characteristics necessary to design an agonist with optimal pharmacological properties. Compound 27a shows high affinity for CB 1R ( K i ( cis-form) = 0.18 μM), with a marked difference in affinity with respect to its inactive " trans-off" form (CB 1R K i trans/cis ratio = 5.4). The novel compounds were evaluated by radioligand binding studies, receptor internalization, sensor receptor activation (GRABeCB2.0), Western blots for analysis of ERK1/2 activation, NanoBiT βarr2 recruitment, and calcium mobilization assays, respectively. The data show that the novel agonist 27a is a candidate for studying the optical modulation of cannabinoid receptors (CBRs), serving as a new molecular tool for investigating the involvement of hCB 1R in disorders associated with the endocannabinoid system.
Original language | English |
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Pages (from-to) | 2410–2435 |
Number of pages | 26 |
Journal | ACS Chemical Neuroscience |
Volume | 13 |
Issue number | 16 |
Early online date | 26 Jul 2022 |
DOIs | |
Publication status | Published - 17 Aug 2022 |
Bibliographical note
FundingThis project was financially supported by the German Research Foundation (Deutsche Forschungsgemeinschaft under DFG DE1546/10-1) and a Ph.D. scholarship for D.A.R.-S. by the German Academic Exchange Service (Deutscher Akademischer Austauschdienst, DAAD). Y.A.R. was granted a scholarship
by the DAAD program “Research stays for university academics and scientists”. A.T. and J.F. were supported by the International Doctoral Program funded within the framework of the Elite Network of Bavaria (grant no. K-BM2013-247). J.N.H. financing support was given by NHS Grampian. The research visit of S.A.M.S. in J.N.H.’s laboratory was also funded by the Elite Network of Bavaria (grant no. KBM-2013-247). M.H.D. was supported by the Research Foundation Flanders (FWO, grant no. 1S54521N). M.J.L. was supported by the German Research Foundation (Deutsche Forschungsgemeinschaft, SFB1423, TPC03).
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Special thanks go to Dr. Rangan Maitra and RTI International for providing the Gαq16 coupled hCB1 and hCB2 CHO-K1 cell lines. The authors thank Nadine Yurdagül-Hemmrich for excellent technical support.
Keywords
- photopharmacology
- CB1 agonist
- G-protein-coupled receptor
- diazocine
- photorimonabant
- optical control