Light‐Switchable Antagonists for the Histamine H₁ Receptor at the Isolated Guinea Pig Ileum

Abstract

The histamine H1 G protein‐coupled receptor (GPCR) plays an important role in allergy and inflammation. Existing drugs that address the H1 receptor differ in their chemical structure, pharmacology, and side effects. Light‐controllable spatial and temporal activity regulation of photochromic H1 ligands may contribute to a better mechanistic understanding and the development of improved correlations between ligand structure and pharmacologic effects. We report photochromic H1 receptor ligands, which were investigated in an organ‐pharmacological assay. Initially, five photochromic azobenzene derivatives of reported dual H1–H4 receptor antagonists were designed, synthesized, photochemically characterized, and organ‐pharmacologically tested on the isolated guinea pig ileum. Among them, one compound [trans‐19: (Z)‐1‐(4‐chlorophenyl)‐1‐(4‐methylpiperazin‐1‐yl)‐N‐(4‐((E)‐phenyldiazenyl)phenyl)methanimine] retained the antagonistic activity of its non‐photochromic lead, and trans–cis isomerization by irradiation induced a fourfold difference in the pharmacological response. Further structural optimization resulted in two bathochromically shifted derivatives of 19 [NO2‐substituted 35 {(Z)‐1‐(4‐chlorophenyl)‐1‐(4‐methylpiperazin‐1‐yl)‐N‐(4‐((E)‐(4‐nitrophenyl)diazenyl)phenyl)methanimine} and SO3−‐substituted 41 {4‐((E)‐(4‐(((Z)‐(4‐chlorophenyl)(4‐methylpiperazin‐1‐yl)methylene)amino)phenyl)diazenyl)benzenesulfonate}], which do not require the use of UV light for photoisomerization and which also have improved solubility and show reduced tissue impairment. The trans isomers of both compounds showed a remarkable increase in antagonistic activity relative to their lead trans‐19; furthermore, a 46‐fold difference in activity on the isolated guinea pig ileum was observed between trans‐ and cis‐35.

Photoresponsive molecular tools for emerging applications of light in medicine

“…However, this resulted in reduced solubility, which was recovered upon the introduction of a sulfonate group on the aromatic ring (compound 102). 103 Further examples showing the effectiveness of adding sulfonate groups for solubility were provided by the groups of Woolley 104 and Feringa. 105 Gratifyingly, it is not always the case that when the activation wavelength is increased it results in solubility issues.…”

Digital Maskless Photolithographic Patterning of DNA-Functionalized Poly(ethylene glycol) Diacrylate Hydrogels with Visible Light Enabling Photodirected Release of Oligonucleotides

“…The techniques outlined in this work suggest that PEGDA- co -DNA hydrogel formulations comprised of camphorquinone and triethanolamine, when combined with digital maskless photolithography, open up new possibilities for assembling structurally complex stimuli-responsive DNA-based biomaterials compatible with a wide array of UV-sensitive photolabile chemistries. − The formation of stable DNA gradients highlights this technique’s potential usefulness for applications requiring patterned substrates that can incorporate DNA-based reaction-diffusion networks and exchange nucleic acid signals between different locations through UV-light activated reactions. Applications of this approach could include photoactivated release of small interfering RNA oligos from implantable tissue scaffolds , and photoregulation of enzymatic circuits .…”

Light‐Triggered Control of Glucocerebrosidase Inhibitors: Towards Photoswitchable Pharmacological Chaperones

“…Under analogous conditions, 1‐(3‐aminopropyl)piperidine ( 11 ) [14] was coupled with 4‐phenylazobenzoylchloride ( 12 ) [15] to yield compound 6 (56 %), bearing an unsubstituted piperidine instead of an iminosugar (Scheme 2).…”

“…The mixture was concentrated under vacuum and then the crude was purified by FCC in the dark (SiO 2 , DCM/MeOH/NH 4 OH (6 %) 4 : 1 : 0.1) to give 3 (123 mg, 0.42 mmol, 72 %) as a colourless oil. R f = 0.18 (DCM/MeOH/ NH 4 OH (6 %) 5 : 1 : 0.1); ½a� 6: A solution of diazo acyl chloride 12 [15] (47 mg, 0.19 mmol) in acetone (1.4 mL) was added to a solution of amine 11 [14] (26 mg, 0.18 mmol) and K 2 CO 3 (11 13: PPh 3 (65 mg, 0.25 mmol) was added to a solution of 14 [6] (70 mg, 0.21 mmol) in dry THF (3.4 mL), and the mixture was stirred at reflux for 50 minutes until water (7 μL) was added and the reaction was left at 50 °C for 18 h. The disappearance of the starting material 14 was assessed via TLC (CH 2 Cl 2 /MeOH/NH 4 OH (6 %) 5 : 1 : 0.1) and the reaction was concentrated under vacuum. The crude residue was purified by flash column chromatography on silica gel (gradient eluent CH 2 Cl 2 /MeOH/ NH 4 OH (6 %) from 10 : 1 : 0.1 to 2 : 1 : 0.1) to give 13 (64 mg, 0.20 mol, 98 %) as a colourless oil.…”

“…6 : A solution of diazo acyl chloride 12 [15] (47 mg, 0.19 mmol) in acetone (1.4 mL) was added to a solution of amine 11 [14] (26 mg, 0.18 mmol) and K 2 CO 3 (11 mg, 0.08 mmol) in H 2 O (0.4 mL). The reaction mixture was stirred at room temperature for 18 h until the disappearance of 11 was assessed by a TLC control (DCM/MeOH/NH 4 OH (6 %) 5 : 1 : 0.1).…”