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Angew Chem Int Ed Engl
2019 Mar 26;5814:4531-4535. doi: 10.1002/anie.201813110.
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A Photoswitchable Agonist for the Histamine H3 Receptor, a Prototypic Family A G-Protein-Coupled Receptor.
Hauwert NJ
,
Mocking TAM
,
Da Costa Pereira D
,
Lion K
,
Huppelschoten Y
,
Vischer HF
,
De Esch IJP
,
Wijtmans M
,
Leurs R
.
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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 H3 receptor (hH3 R). Upon illumination, key compound 65 decreases its affinity for the hH3 R by 8.5-fold and its potency in hH3 R-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 hH3 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.
Figure 1. General design and concept of photoswitchable H3R full agonists.
Scheme 1. General synthetic scheme for photoswitchable H3R agonists. See the Supporting Information for detailed experimental procedures.
Figure 2. A)â Representative part of 1Hâ NMR spectra of 10â mm
65 in [D6]DMSO illuminated at 360±20â nm displayed at various time points (seconds). The presented peak belongs to the hydrogen atoms explicitly drawn in the structure shown above the spectrum. Full spectra are available in Figureâ S4 in the Supporting Information. B)â Representative part of LCâMS chromatograms belonging to the illuminated NMR sample in Figureâ 2âA. Full chromatograms are available in Figureâ S5 in the Supporting Information. C)â UV/Vis spectra of 25â μm of 65 in 50â mm TrisâHCl pHâ 7.4 buffer + 1â% [D6]DMSO. PSS cis represents a sample which has been illuminated for 300â s using 360±20â nm light. PSS trans represents subsequent illumination for 300â s using 434±9â nm light. D)â Repeated isomerization of 25â μm of 65 in 50â mm TrisâHCl pHâ 7.4 buffer + 1â% [D6]DMSO analyzed at 320â nm. PSS cis was obtained by illuminating 65 for 40â s at 360±20â nm. PSS trans was obtained by illuminating 65 for 40â s at 434±9â nm. E)â Absorbance at 320â nm of 25â μm of 65 in 50â mm TrisâHCl pHâ 7.4 buffer + 1â% [D6]DMSO. UV/Vis spectra were obtained at 1â s intervals under alternating illumination at 360±20â nm and 434±9â nm perpendicular to the light source of the UV/Vis spectrometer.
Figure 3. Representative curves of 65 (A) in competition binding with [3H]âNAMH or (B) in Gi protein activation, as measured by [35S]âGTPγS accumulation on HEK293T cell homogenates transiently expressing hH3R. Black lines refer to a sample containing more than 99â% trans
65, while magenta lines refer to a sample of 65 illuminated to PSS cis with 360±20â nm prior to the assay. C)â Schematic drawing of the TEVC setup used for dynamic hH3R and GIRK current activation in Xenopus laevis oocytes expressing hH3R and GIRK. D)â Representative part of a GIRKâmediated current trace during continuous perfusion with 1â μm
65, while illuminating the oocyte with alternating 360±20 and 434±9â nm wavelength, as measured by TEVC. Error bars shown are mean±SD.
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