Light‐Switchable Antagonists for the Histamine H 1 Receptor at the Isolated Guinea Pig Ileum

The histamine H 1 G protein‐coupled receptor (GPCR) plays an important role in allergy and inflammation. Existing drugs that address the H 1 receptor differ in their chemical structure, pharmacology, and side effects. Light‐controllable spatial and temporal activity regulation of photochromic H 1 ligands may contribute to a better mechanistic understanding and the development of improved correlations between ligand structure and pharmacologic effects. We report photochromic H 1 receptor ligands, which were investigated in an organ‐pharmacological assay. Initially, five photochromic azobenzene derivatives of reported dual H 1 –H 4 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 [NO 2 ‐substituted 35 {( Z )‐1‐(4‐chlorophenyl)‐1‐(4‐methylpiperazin‐1‐yl)‐ N ‐(4‐(( E )‐(4‐nitrophenyl)diazenyl)phenyl)methanimine} and SO 3 − ‐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 .