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

Jones, B. J., Scopelliti, R., Tomas, A., Bloom, S. R., Hodson, D. J., & Broichhagen, J. (2017). Potent prearranged positive allosteric modulators of the glucagon-like peptide-1 receptor. ChemistryOpen, 6(4), 501-505. doi:10.1002/open.201700062.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-002D-C81F-7 Version Permalink: http://hdl.handle.net/11858/00-001M-0000-002D-D8B1-B
Genre: Journal Article

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ChemistryOpen_6_2017_501.pdf (Any fulltext), 2MB
 
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https://doi.org/10.1002/open.201700062 (Any fulltext)
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 Creators:
Jones, Ben J., Author
Scopelliti, Rosario, Author
Tomas, Alejandra, Author
Bloom, Stephen R., Author
Hodson, David J., Author
Broichhagen, Johannes1, Author              
Affiliations:
1Chemical Biology, Max Planck Institute for Medical Research, Max Planck Society, ou_2364732              

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Free keywords: BETP; G protein-coupled receptors; allosterism; glucagon-like peptide-1 receptors; glucagon-like peptides; stilbene
 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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Language(s): eng - English
 Dates: 2017-03-272017-06-052017-06-052017-08-01
 Publication Status: Published in print
 Pages: 5
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Degree: -

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Title: ChemistryOpen
Source Genre: Journal
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Publ. Info: Weinheim : Wiley-VCH
Pages: - Volume / Issue: 6 (4) Sequence Number: - Start / End Page: 501 - 505 Identifier: ISSN: 2191-1363
CoNE: https://pure.mpg.de/cone/journals/resource/2191-1363