Fluorination of Photoswitchable Muscarinic Agonists Tunes Receptor Pharmacology and Photochromic Properties

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.