Journal
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
Volume 58, Issue 14, Pages 4531-4535Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.201813110
Keywords
agonism; dynamic modulation; H3R; photopharmacology; VUF15000
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Funding
- Netherlands Organisation for Scientific Research (NWO) [718.014.002]
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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.
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