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Selective Photoswitchable Allosteric Agonist of a G Protein-Coupled Receptor
- Source :
- Journal of the American Chemical Society, vol 143, iss 24, Journal of the American Chemical Society
- Publication Year :
- 2021
- Publisher :
- eScholarship, University of California, 2021.
-
Abstract
- G protein-coupled receptors (GPCRs) are the most common targets of drug discovery. However, the similarity between related GPCRs combined with the complex spatiotemporal dynamics of receptor activation in vivo has hindered drug development. Photopharmacology offers the possibility of using light to control the location and timing of drug action by incorporating a photoisomerizable azobenzene into a GPCR ligand, enabling rapid and reversible switching between an inactive and active configuration. Recent advances in this area include (i) photoagonists and photoantagonists that directly control receptor activity but are nonselective because they bind conserved sites, and (ii) photoallosteric modulators that bind selectively to nonconserved sites but indirectly control receptor activity by modulating the response to endogenous ligand. In this study, we designed a photoswitchable allosteric agonist that targets a nonconserved allosteric site for selectivity and activates the receptor on its own to provide direct control. This work culminated in the development of aBINA, a photoswitchable allosteric agonist that selectively activates the Gi/o-coupled metabotropic glutamate receptor 2 (mGluR2). aBINA is the first example of a new class of precision drugs for GPCRs and other clinically important signaling proteins.
- Subjects :
- Agonist
medicine.drug_class
1.1 Normal biological development and functioning
Allosteric regulation
Drug action
010402 general chemistry
Ligands
01 natural sciences
Biochemistry
Catalysis
Receptors, G-Protein-Coupled
G-Protein-Coupled
Colloid and Surface Chemistry
Allosteric Regulation
Underpinning research
Receptors
medicine
Benzene Derivatives
Humans
Receptor
G protein-coupled receptor
Chemistry
Drug discovery
Communication
General Chemistry
Ligand (biochemistry)
Photochemical Processes
0104 chemical sciences
Chemical Sciences
Biophysics
Generic health relevance
Metabotropic glutamate receptor 2
Subjects
Details
- Database :
- OpenAIRE
- Journal :
- Journal of the American Chemical Society, vol 143, iss 24, Journal of the American Chemical Society
- Accession number :
- edsair.doi.dedup.....4c98f30636255b31e62249f1b1c93780