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Related Concept Videos

Allosteric Regulation01:08

Allosteric Regulation

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Allosteric regulation of enzymes occurs when the binding of an effector molecule to a site that is different from the active site causes a change in the enzymatic activity. This alternate site is called an allosteric site, and an enzyme can contain more than one of these sites. Allosteric regulation can either be positive or negative, resulting in an increase or decrease in enzyme activity. Most enzymes that display allosteric regulation are metabolic enzymes involved in the degradation or...
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A Kinetic Fluorescence-based Ca2+ Mobilization Assay to Identify G Protein-coupled Receptor Agonists, Antagonists, and Allosteric Modulators
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Profiling Allosteric Modulators of CB1R with an Allosteric Fluoroprobe.

Miroslav Kosar1, Themiya Perera2, Rudolf L Z Ganzoni1

  • 1Laboratorium für Organische Chemie, ETH Zürich, Vladimir-Prelog-Weg 3, 8093, Zürich, Switzerland.

Angewandte Chemie (International Ed. in English)
|February 18, 2025
PubMed
Summary

Researchers developed a novel allosteric fluoroprobe and assay to directly profile cannabinoid receptor type 1 (CB1R) allosteric modulators. This method distinguishes between allosteric and orthosteric ligands, clarifying cannabidiol

Keywords:
Allosteric modulatorsCannabinoid Receptor Type 1 (CB1R)FluoroprobeG protein-coupled receptorsTR-FRET

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Area of Science:

  • Pharmacology and Neuroscience
  • Biochemistry and Molecular Biology

Background:

  • Allosteric modulation of cannabinoid receptor type 1 (CB1R) presents a novel therapeutic strategy distinct from traditional orthosteric ligand (OL) approaches.
  • Current methods for characterizing CB1R allosteric modulators (AMs) rely on co-incubation with OLs, hindering the independent assessment of allosteric and orthosteric ligand contributions.
  • Existing characterization techniques lack the precision to isolate the specific binding and functional effects of CB1R AMs.

Purpose of the Study:

  • To develop the first allosteric fluoroprobe and Förster Resonance Energy Transfer (FRET)-based assay for direct profiling of CB1R AMs.
  • To enable the differentiation and pharmacological characterization of allosteric versus orthosteric ligands at the CB1R.
  • To resolve ambiguities regarding the binding interactions of cannabidiol (CBD) at the CB1R.

Main Methods:

  • Development of a novel allosteric fluoroprobe targeting the CB1R.
  • Establishment of a FRET-based assay for direct measurement of allosteric ligand binding.
  • Application of the assay to profile CB1R AMs independently of OLs and to investigate CBD binding.

Main Results:

  • The developed allosteric fluoroprobe and FRET assay successfully allowed direct profiling of CB1R AMs without the need for OL co-incubation.
  • The assay effectively differentiated between allosteric and orthosteric ligands, providing precise pharmacological profiles.
  • Cannabidiol (CBD) was demonstrated to interact with both the allosteric and orthosteric sites of CB1R with comparable affinities (pKi=5.34 and 5.67, respectively).

Conclusions:

  • The novel allosteric fluoroprobe and FRET assay represent a significant advancement for the direct characterization of CB1R allosteric modulators.
  • This methodology overcomes previous limitations by enabling the isolation and profiling of allosteric effects independent of orthosteric ligands.
  • The findings clarify the dual binding nature of CBD at the CB1R, offering crucial insights for its therapeutic applications.