TY - JOUR
T1 - A Photoswitchable Agonist for the Histamine H
3
Receptor, a Prototypic Family A G-Protein-Coupled Receptor
AU - Hauwert, Niels J.
AU - Mocking, Tamara A.M.
AU - Da Costa Pereira, Daniel
AU - Lion, Ken
AU - Huppelschoten, Yara
AU - Vischer, Henry F.
AU - De Esch, Iwan J.P.
AU - Wijtmans, Maikel
AU - Leurs, Rob
PY - 2019/3/26
Y1 - 2019/3/26
N2 -
Spatiotemporal control over biochemical signaling processes involving G protein-coupled receptors (GPCRs) is highly desired for dissecting their complex intracellular signaling. We developed sixteen photoswitchable ligands for the human histamine H
3
receptor (hH
3
R). Upon illumination, key compound 65 decreases its affinity for the hH
3
R by 8.5-fold and its potency in hH
3
R-mediated G
i
protein activation by over 20-fold, with the trans and cis isomer both acting as full agonist. In real-time two-electrode voltage clamp experiments in Xenopus oocytes, 65 shows rapid light-induced modulation of hH
3
R activity. Ligand 65 shows good binding selectivity amongst the histamine receptor subfamily and has good photolytic stability. In all, 65 (VUF15000) is the first photoswitchable GPCR agonist confirmed to be modulated through its affinity and potency upon photoswitching while maintaining its intrinsic activity, rendering it a new chemical biology tool for spatiotemporal control of GPCR activation.
AB -
Spatiotemporal control over biochemical signaling processes involving G protein-coupled receptors (GPCRs) is highly desired for dissecting their complex intracellular signaling. We developed sixteen photoswitchable ligands for the human histamine H
3
receptor (hH
3
R). Upon illumination, key compound 65 decreases its affinity for the hH
3
R by 8.5-fold and its potency in hH
3
R-mediated G
i
protein activation by over 20-fold, with the trans and cis isomer both acting as full agonist. In real-time two-electrode voltage clamp experiments in Xenopus oocytes, 65 shows rapid light-induced modulation of hH
3
R activity. Ligand 65 shows good binding selectivity amongst the histamine receptor subfamily and has good photolytic stability. In all, 65 (VUF15000) is the first photoswitchable GPCR agonist confirmed to be modulated through its affinity and potency upon photoswitching while maintaining its intrinsic activity, rendering it a new chemical biology tool for spatiotemporal control of GPCR activation.
KW - agonism
KW - dynamic modulation
KW - H R
KW - photopharmacology
KW - VUF15000
UR - http://www.scopus.com/inward/record.url?scp=85062349665&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85062349665&partnerID=8YFLogxK
U2 - 10.1002/anie.201813110
DO - 10.1002/anie.201813110
M3 - Article
AN - SCOPUS:85062349665
SN - 1433-7851
VL - 58
SP - 4531
EP - 4535
JO - Angewandte Chemie. International Edition
JF - Angewandte Chemie. International Edition
IS - 14
ER -