Fluorination of Photoswitchable Muscarinic Agonists Tunes Receptor Pharmacology and Photochromic Properties

Luca Agnetta, Marcel Bermudez, Fabio Riefolo, Carlo Matera, Enrique Claro, Regina Messerer, Timo Littmann, Gerhard Wolber, Ulrike Holzgrabe, Michael Decker

Research output: Contribution to journalArticleResearch

5 Citations (Scopus)

Abstract

© 2019 American Chemical Society. Red-shifted azobenzene scaffolds have emerged as useful molecular photoswitches to expand potential applications of photopharmacological tool compounds. As one of them, tetra-ortho-fluoro azobenzene is well compatible for the design of visible-light-responsive systems, providing stable and bidirectional photoconversions and tissue-compatible characteristics. Using the unsubstituted azobenzene core and its tetra-ortho-fluorinated analogue, we have developed a set of uni- and bivalent photoswitchable toolbox derivatives of the highly potent muscarinic acetylcholine receptor agonist iperoxo. We investigated the impact of the substitution pattern on receptor activity and evaluated the different binding modes. Compounds 9b and 15b show excellent photochemical properties and biological activity as fluorination of the azobenzene core alters not only the photochromic behavior but also the pharmacological profile at the muscarinic M1 receptor. These findings demonstrate that incorporation of fluorinated azobenzenes not just may alter photophysical properties but can exhibit a considerably different biological profile that has to be carefully investigated.
Original languageEnglish
Pages (from-to)3009-3020
JournalJournal of Medicinal Chemistry
Volume62
DOIs
Publication statusPublished - 28 Mar 2019

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