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Sign Inversion in Photopharmacology: Incorporation of Cyclic Azobenzenes in Photoswitchable Potassium Channel Blockers and Openers

preprint
submitted on 18.04.2019 and posted on 19.04.2019 by Julie Trads, Katharina Hüll, Bryan Matsuura, Laura Laprell, Timm Fehrentz, Nicole Görldt, Krystian A. Kozek, David Weaver, Nikolaj Klöcker, David Barber, Dirk Trauner
Photopharmacology relies on ligands that change their pharmacodynamics upon photoisomerization. Many of these ligands are azobenzenes that are thermodynamically more stable in their elongated transconfiguration, which predominates in the dark. Often, they are biologically active in this form and lose activity upon irradiation and photoisomerization to their cis-isomer. Recently, cyclic azobenzenes, so-called diazocines, have emerged. They are thermodynamically more stable in their bent cis­‑form than in their elongated trans-form. Incorporation of these switches into a variety of photopharmaceuticals could convert dark-active ligands into dark-inactive ligands, which is preferred in most biological applications. This “pharmacological sign-inversion” is demonstrated for a photochromic blocker of voltage-gated potassium channels, termed CAL, and a photochromic opener of G-protein-coupled inwardly rectifying potassium (GIRK) channels, termed CLOGO.

Funding

J.B.T. thanks the Danish National Research Foundation Center for DNA Nanotechnology (DNRF81) and Aarhus University, Faculty of Science and Technology for financial support. K.H. thanks the Studienstiftung des deutschen Volkes for a PhD scholarship. B.S.M. thanks the Alexander von Humboldt Foundation for a postdoctoral research fellowship. N.K. was supported by the SFB1116, TPA01 (Deutsche Forschungsgemeinschaft). D.M.B. thanks the European Commission for a Marie Skłodowska-Curie Intra-European Fellowship (PIEF-GA-2013-627990). D.T. was supported by the European Research Council (Advanced Grant 268795) and thanks the Centre for Integrated Protein Science Munich (CIPSM).

History

Email Address of Submitting Author

dirktrauner@nyu.edu

Institution

New York University

Country

USA

ORCID For Submitting Author

0000-0002-6782-6056

Declaration of Conflict of Interest

CDW is an owner of WaveFront Biosciences, maker of the thallium-sensitive fluorescent dye, Thallos, and the kinetic imaging plate reader, Panoptic, used in this manuscript. No other authors have any conflicts of interest to declare.

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