Details

Autor(en) / Beteiligte

• Rustler, Karin
• Pockes, Steffen
• König, Burkhard

Titel

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

Ist Teil von

• ChemMedChem, 2019-03, Vol.14 (6), p.636-644

Ort / Verlag

Weinheim: Wiley Subscription Services, Inc

Erscheinungsjahr

2019

Quelle

Wiley-Blackwell Journals

Beschreibungen/Notizen

• 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. Organ‐photopharmacology: We report the design, synthesis, and photophysical characterization of seven photochromic oxazepine derivatives, as well as the establishment of an organ‐pharmacological assay compatible with continuous tissue irradiation. These light‐controllable histamine H1R antagonists were found to be active on isolated guinea pig ilea. The trans isomer of compound 35 shows a 46‐fold higher antagonistic activity than the cis isomer.