A Photoswitchable Agonist for the Histamine H3 Receptor,a Prototypic Family A G‐Protein‐Coupled Receptor |
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Authors: | Niels J Hauwert Tamara A M Mocking Daniel DaCostaPereira Ken Lion Yara Huppelschoten Henry F Vischer Iwan J P DeEsch Maikel Wijtmans Rob Leurs |
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Institution: | Niels J. Hauwert,Tamara A. M. Mocking,Daniel Da Costa Pereira,Ken Lion,Yara Huppelschoten,Henry F. Vischer,Iwan J. P. De Esch,Maikel Wijtmans,Rob Leurs |
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Abstract: | 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 H3 receptor (hH3R). Upon illumination, key compound 65 decreases its affinity for the hH3R by 8.5‐fold and its potency in hH3R‐mediated Gi 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 hH3R 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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Keywords: | Agonismus Dynamische Modulation H3R Photopharmakologie VUF15000 |
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