A Photoswitchable Agonist for the Histamine H                         
                        3
                                                  Receptor, a Prototypic Family A G-Protein-Coupled Receptor

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

doi:10.1002/anie.201813110

A Photoswitchable Agonist for the Histamine H ₃ Receptor, a Prototypic Family A G-Protein-Coupled Receptor

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

^*Corresponding author for this work

Research output: Contribution to Journal › Article › Academic › peer-review

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 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.

Original language	English
Pages (from-to)	4531-4535
Number of pages	5
Journal	Angewandte Chemie. International Edition
Volume	58
Issue number	14
Early online date	8 Feb 2019
DOIs	https://doi.org/10.1002/anie.201813110
Publication status	Published - 26 Mar 2019

Funding

We acknowledge The Netherlands Organisation for Scientific Research (NWO) for financial support (TOPPUNT, “7 ways to 7TMR modulation (7-to-7)”, 718.014.002). All authors participate in the European Cooperation in Science and Technology Action CM1207 [GPCR-Ligand Interactions, Structures, and Transmembrane Signaling: A European Research Network (GLISTEN)]. We thank Hans Custers for HRMS analyses, Andrea van de Stolpe for setting up the photochemistry equipment and Fons Lefeber (Leiden University) for NMR assistance. Kristoffer Sahlholm (Karolinska institute) is kindly acknowledged for providing the pcDNA3.1-Kir3.1 and -Kir3.4 plasmids.

Funders	Funder number
European Cooperation in Science and Technology	CM1207
Universiteit Leiden
Nederlandse Organisatie voor Wetenschappelijk Onderzoek	7-to-7, 718.014.002
Karolinska Institutet

Keywords

agonism
dynamic modulation
H R
photopharmacology
VUF15000

Access to Document

10.1002/anie.201813110

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Cite this

Hauwert, N. J., Mocking, T. A. M., Da Costa Pereira, D., Lion, K., Huppelschoten, Y., Vischer, H. F., De Esch, I. J. P., Wijtmans, M., & Leurs, R. (2019). A Photoswitchable Agonist for the Histamine H ₃ Receptor, a Prototypic Family A G-Protein-Coupled Receptor. Angewandte Chemie. International Edition, 58(14), 4531-4535. https://doi.org/10.1002/anie.201813110

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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 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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Hauwert, NJ, Mocking, TAM, Da Costa Pereira, D, Lion, K, Huppelschoten, Y, Vischer, HF , De Esch, IJP , Wijtmans, M & Leurs, R 2019, 'A Photoswitchable Agonist for the Histamine H ₃ Receptor, a Prototypic Family A G-Protein-Coupled Receptor', Angewandte Chemie. International Edition, vol. 58, no. 14, pp. 4531-4535. https://doi.org/10.1002/anie.201813110

A Photoswitchable Agonist for the Histamine H ₃ Receptor, a Prototypic Family A G-Protein-Coupled Receptor. / Hauwert, Niels J.; Mocking, Tamara A.M.; Da Costa Pereira, Daniel et al.
In: Angewandte Chemie. International Edition, Vol. 58, No. 14, 26.03.2019, p. 4531-4535.

Research output: Contribution to Journal › Article › Academic › peer-review

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AU - Huppelschoten, Yara

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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.

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Hauwert NJ, Mocking TAM, Da Costa Pereira D, Lion K, Huppelschoten Y, Vischer HF et al. A Photoswitchable Agonist for the Histamine H ₃ Receptor, a Prototypic Family A G-Protein-Coupled Receptor. Angewandte Chemie. International Edition. 2019 Mar 26;58(14):4531-4535. Epub 2019 Feb 8. doi: 10.1002/anie.201813110