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Potent prearranged positive allosteric modulators of the glucagon-like peptide-1 receptor

Authors
  • Jones, BJ
  • Scopelliti, R
  • Tomas, A
  • Bloom, SR
  • Hodson, DJ
  • Broichhagen, J
Publication Date
Mar 27, 2017
Identifiers
DOI: 10.1002/open.201700062
OAI: oai:spiral.imperial.ac.uk:10044/1/51280
Source
Spiral - Imperial College Digital Repository
Keywords
License
Unknown

Abstract

Drugs that allosterically modulate G protein-coupled receptor (GPCR) activity display higher specificity and may improve disease treatment. However, the rational design of compounds that target the allosteric site is difficult, as conformations required for receptor activation are poorly understood. Guided by photopharmacology, a set of prearranged positive allosteric modulators (PAMs) with restricted degrees of freedom was designed and tested against the glucagon-like peptide-1 receptor (GLP-1R), a GPCR involved in glucose homeostasis. Compounds incorporating a trans-stilbene comprehensively outperformed those with a cis-stilbene, as well as the benchmark BETP, as GLP-1R PAMs. We also identified major effects of ligand conformation on GLP-1R binding kinetics and signal bias. Thus, we describe a photopharmacology-directed approach for rational drug design, and introduce a new class of stilbene-containing PAM for the specific regulation of GPCR activity.

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