TY - JOUR
T1 - Photoswitching the Efficacy of a Small-Molecule Ligand for a Peptidergic GPCR
T2 - from Antagonism to Agonism
AU - Gómez-Santacana, Xavier
AU - de Munnik, Sabrina M.
AU - Vijayachandran, Prashanna
AU - Da Costa Pereira, Daniel
AU - Bebelman, Jan Paul M.
AU - de Esch, Iwan J.P.
AU - Vischer, Henry F.
AU - Wijtmans, Maikel
AU - Leurs, Rob
PY - 2018/9/3
Y1 - 2018/9/3
N2 - For optical control of GPCR function, we set out to develop small-molecule ligands with photoswitchable efficacy in which both configurations bind the target protein but exert distinct pharmacological effects, that is, stimulate or antagonize GPCR activation. Our design was based on a previously identified efficacy hotspot for the peptidergic chemokine receptor CXCR3 and resulted in the synthesis and characterization of five new azobenzene-containing CXCR3 ligands. G protein activation assays and real-time electrophysiology experiments demonstrated photoswitching from antagonism to partial agonism and even to full agonism (compound VUF16216). SAR evaluation suggests that the size and electron-donating properties of the substituents on the inner aromatic ring are important for the efficacy photoswitching. These compounds are the first GPCR azo ligands with a nearly full efficacy photoswitch and may become valuable pharmacological tools for the optical control of peptidergic GPCR signaling.
AB - For optical control of GPCR function, we set out to develop small-molecule ligands with photoswitchable efficacy in which both configurations bind the target protein but exert distinct pharmacological effects, that is, stimulate or antagonize GPCR activation. Our design was based on a previously identified efficacy hotspot for the peptidergic chemokine receptor CXCR3 and resulted in the synthesis and characterization of five new azobenzene-containing CXCR3 ligands. G protein activation assays and real-time electrophysiology experiments demonstrated photoswitching from antagonism to partial agonism and even to full agonism (compound VUF16216). SAR evaluation suggests that the size and electron-donating properties of the substituents on the inner aromatic ring are important for the efficacy photoswitching. These compounds are the first GPCR azo ligands with a nearly full efficacy photoswitch and may become valuable pharmacological tools for the optical control of peptidergic GPCR signaling.
KW - azo compounds
KW - efficacy photoswitching
KW - G protein-coupled receptors
KW - photochromism
KW - photopharmacology
UR - http://www.scopus.com/inward/record.url?scp=85052536871&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85052536871&partnerID=8YFLogxK
U2 - 10.1002/anie.201804875
DO - 10.1002/anie.201804875
M3 - Article
SN - 1433-7851
VL - 57
SP - 11608
EP - 11612
JO - Angewandte Chemie. International Edition
JF - Angewandte Chemie. International Edition
IS - 36
ER -
