Fluorination of Photoswitchable Muscarinic Agonists Tunes Receptor Pharmacology and Photochromic Properties

Abstract

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.

Two-photon absorption and two-photon-induced isomerization of azobenzene compounds

“…40,44 This makes them likely to t for photobiological applications in which intermolecular p-stacking interactions with the host molecule are required. 45…”

Light-Controlled Lyotropic Liquid Crystallinity of Polyaspartates

“…The product was isolated by fractional distillation under reduced pressure (80 °C bottom temperature, 65 °C top temperature, 0.2 bar) and obtained as colourless liquid (21.1 g, 0.16 mol, 97 % purity remainder is diethyl ether, 46 % yield). (5) According to a literature-known procedure 3 , 2,6-difluorophenyl diazonium salt (5) was prepared from 2,6-difluoroaniline (3, 59.9 g, 0.45 mol, 1.0 eq. ), tetrafluoroboric acid solution (50 % (w/w) in water, 0.15 L, 1.22 mol, 2.7 eq.)…”

“…25 -7.18 (m, 1H, HZ-8),6.87 (dd, 3 JHF = 8.2 Hz, 3 JHH = 8.2 Hz, 2H, HZ-7,Z-7'),6.67 (d, 3 JHF = 9.3 Hz, 2H, HZ-3,Z-3'), 2.43 (s, 3H, HE-9, 3 %(n/n)), 2.31 (s, 3H, HZ-9, 97 %(n/n)) ppm. (literature data4,5 measured in DMSO-d6 and CDCl3 is unassigned)19 F NMR: (CDCl 3 , 659 MHz, 279 K) δ = -119.5 to -119.6 (m, 2F, F Z-11,Z-11' ), -120.2 to -120.3 (m, 2F, F Z-10,Z-10' ) ppm. (literature data 4 measured in DMSO-d 6 is unassigned) 13 C{ 1 H} NMR: (CDCl3, 151 MHz, 279 K) δ = 151.7 (dd, 1 JCF = 253.7 Hz, 3 JCF = 5.4 Hz, 2C, CZ-6,Z-6'), 151.4 (dd, 1 JCF = 253.1 Hz, 3 JCF = 6.1 Hz, 2C, CZ-2,Z-2'), 141.6 (t, 3 JCF = 9.2 Hz, 1C, CZ-4), 132.0 (t, 2 JCF = 17.1 Hz, 1C, CZ-5), 129.7 (t, 3 JCF = 9.4 Hz, 1C, CZ-8), 129.4 (t, 2 JCF = 17.2 Hz, 1C, CZ-1), 112.5 (dd, 2 JCF = 19.8 Hz, 4 JCF = 3.2 Hz, 2C, CZ-3,Z-3'), 112.0 (dd, 2 JCF = 19.9 Hz, 4 JCF = 3.7 Hz, 2C, CZ-7,Z-7'), 21.4 (t, 4 JCF = 1.7 Hz, 1C, CZ-9) ppm.…”

Novel BQCA‐ and TBPB‐Derived M1 Receptor Hybrid Ligands: Orthosteric Carbachol Differentially Regulates Partial Agonism

“…[19] This approachh as the advantage that it is not reliant on the endogenous neurotransmitter and that biased signaling by activation of as pecific downstream signali sp ossible via as ingle molecule. [21][22][23][24] Furthermore,t he design of the connecting linker represents ac hallenge not only for dualsteric GPCR ligands, but for any kind of bivalent ligand.F or this reason,r andomw alk as well as computational approaches have been used to guide linker design. For this purpose, the connection points have to be chosen carefully in order to avoid alteration of essential functional groups responsible for receptor binding and function.…”

“…[20] In earlier studies, av ariety of dualsteric M 1 ligands have been developed, includingap hotoswitchable BQCA-iperoxoh ybrid. [21][22][23][24] Furthermore,t he design of the connecting linker represents ac hallenge not only for dualsteric GPCR ligands, but for any kind of bivalent ligand.F or this reason,r andomw alk as well as computational approaches have been used to guide linker design. [25] Because the orthosteric and allosteric binding pockets of the M 1 receptor are separated by the so-called "tyrosine lid" formed by three tyrosine residues (Figure1), dualsteric ligands have to bridge these two sites by al inker.W eh ave chosen three different linker lengths for this study.F irst, aC 3 -alkyl chain linker represents the shortestp ossible linker length to bypasst he tyrosine lid.…”