Issue 19, 2022

Detection of cannabinoid receptor type 2 in native cells and zebrafish with a highly potent, cell-permeable fluorescent probe

Abstract

Despite its essential role in the (patho)physiology of several diseases, CB2R tissue expression profiles and signaling mechanisms are not yet fully understood. We report the development of a highly potent, fluorescent CB2R agonist probe employing structure-based reverse design. It commences with a highly potent, preclinically validated ligand, which is conjugated to a silicon-rhodamine fluorophore, enabling cell permeability. The probe is the first to preserve interspecies affinity and selectivity for both mouse and human CB2R. Extensive cross-validation (FACS, TR-FRET and confocal microscopy) set the stage for CB2R detection in endogenously expressing living cells along with zebrafish larvae. Together, these findings will benefit clinical translatability of CB2R based drugs.

Graphical abstract: Detection of cannabinoid receptor type 2 in native cells and zebrafish with a highly potent, cell-permeable fluorescent probe

Supplementary files

Article information

Article type
Edge Article
Submitted
29 noy 2021
Accepted
22 yan 2022
First published
01 apr 2022
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY-NC license

Chem. Sci., 2022,13, 5539-5545

Detection of cannabinoid receptor type 2 in native cells and zebrafish with a highly potent, cell-permeable fluorescent probe

T. Gazzi, B. Brennecke, K. Atz, C. Korn, D. Sykes, G. Forn-Cuni, P. Pfaff, R. C. Sarott, M. V. Westphal, Y. Mostinski, L. Mach, M. Wasinska-Kalwa, M. Weise, B. L. Hoare, T. Miljuš, M. Mexi, N. Roth, E. J. Koers, W. Guba, A. Alker, A. C. Rufer, E. A. Kusznir, S. Huber, C. Raposo, E. A. Zirwes, A. Osterwald, A. Pavlovic, S. Moes, J. Beck, M. Nettekoven, I. Benito-Cuesta, T. Grande, F. Drawnel, G. Widmer, D. Holzer, T. van der Wel, H. Mandhair, M. Honer, J. Fingerle, J. Scheffel, J. Broichhagen, K. Gawrisch, J. Romero, C. J. Hillard, Z. V. Varga, M. van der Stelt, P. Pacher, J. Gertsch, C. Ullmer, P. J. McCormick, S. Oddi, H. P. Spaink, M. Maccarrone, D. B. Veprintsev, E. M. Carreira, U. Grether and M. Nazaré, Chem. Sci., 2022, 13, 5539 DOI: 10.1039/D1SC06659E

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