Profiling Allosteric Modulators of CB <sub>1</sub> R with an Allosteric Fluoroprobe

Abstract Allosteric modulation of cannabinoid receptor type 1 (CB 1 R) offers a promising alternative to conventional therapeutic approaches using orthosteric ligands (OLs). Currently, CB 1 R allosteric modulators (AMs) are characterized based on their ability to modulate binding or functional response of OLs, preventing isolation of individual contributions by allosteric and orthosteric ligands. Herein, we develop the first allosteric fluoroprobe and attendant FRET‐based assay allowing for the direct profiling of CB 1 R AMs without coincubation with an OL. Our allosteric tracer enables differentiation of allosteric and orthosteric ligands as well as their pharmacological profiling at CB 1 R. The utility of this work is highlighted by addressing ambiguities surrounding the binding of cannabidiol (CBD). CBD was found to interact with both allosteric and orthosteric sites of CB 1 R with comparable affinity (p K i =5.34 and 5.67, respectively).

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Publication Details

Journal
Angewandte Chemie
Published
2025-02-18
DOI
https://doi.org/10.1002/ange.202421885
Primary Topic
Diet and metabolism studies
Type
article
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article

Profiling Allosteric Modulators of CB 1 R with an Allosteric Fluoroprobe

Dmitry B. Veprintsev, Rosa Maria Vitale, Wolfgang Guba, Rudolf L. Z. Ganzoni et al.
Angewandte Chemie
Diet and metabolism studies
article

Profiling Allosteric Modulators of CB 1 R with an Allosteric Fluoroprobe

Dmitry B. Veprintsev, Rosa Maria Vitale, Wolfgang Guba, Rudolf L. Z. Ganzoni, David A. Sykes, Erick M. Carreira, Miroslav Kosar, Uwe Grether, Alessia Ligresti, Roman C. Sarott, Arne C. Rufer, Themiya Perera
article en

Abstract

Abstract Allosteric modulation of cannabinoid receptor type 1 (CB 1 R) offers a promising alternative to conventional therapeutic approaches using orthosteric ligands (OLs). Currently, CB 1 R allosteric modulators (AMs) are characterized based on their ability to modulate binding or functional response of OLs, preventing isolation of individual contributions by allosteric and orthosteric ligands. Herein, we develop the first allosteric fluoroprobe and attendant FRET‐based assay allowing for the direct profiling of CB 1 R AMs without coincubation with an OL. Our allosteric tracer enables differentiation of allosteric and orthosteric ligands as well as their pharmacological profiling at CB 1 R. The utility of this work is highlighted by addressing ambiguities surrounding the binding of cannabidiol (CBD). CBD was found to interact with both allosteric and orthosteric sites of CB 1 R with comparable affinity (p K i =5.34 and 5.67, respectively).

Angewandte ChemieVol. 137(20)
Roche (Switzerland) (CH), University of Nottingham (GB), University of the Basque Country (ES), ETH Zurich (CH), Institute of Applied Science and Intelligent Systems (IT), National Research Council (IT)
Openalex Percentile: Top 96%
Diet and metabolism studies
DOISourceOpenAlex
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