Potent prearranged positive allosteric modulators of the glucagon-like peptide-1 receptor
Author(s)
Type
Journal Article
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.
Date Issued
2017-06-05
Date Acceptance
2017-03-27
Citation
ChemistryOpen, 2017, 6 (4), pp.501-505
ISSN
2191-1363
Publisher
Wiley
Start Page
501
End Page
505
Journal / Book Title
ChemistryOpen
Volume
6
Issue
4
Copyright Statement
© 2017 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Identifier
http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000407167100010&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
Subjects
Science & Technology
Physical Sciences
Chemistry, Multidisciplinary
Chemistry
allosterism
BETP
glucagon-like peptides
glucagon-like peptide-1 receptors
G protein-coupled receptors
stilbene
PROTEIN-COUPLED RECEPTORS
DRUG DISCOVERY
PHYSIOLOGY
BINDING
GPCRS
TIME
Publication Status
Published