Abstract
Novel fluorescent chalcone-based ligands at human histamine H3 receptors (hH3R) have been designed, synthesized, and characterized. Compounds described are non-imidazole analogs of ciproxifan with a tetralone motif. Tetralones as chemical precursors and related fluorescent chalcones exhibit affinities at hH3R in the same concentration range like the reference antagonist ciproxifan (hH3R pKi value of 7.2). Fluorescence characterization of our novel ligands shows emission maxima about 570 nm for yellow fluorescent chalcones and ≥600 nm for the red fluorescent derivatives. Interferences to cellular autofluorescence could be excluded. All synthesized chalcone compounds could be used to visualize hH3R proteins in stably transfected HEK-293 cells using confocal laser scanning fluorescence microscopy. These novel fluorescent ligands possess high potential to be used as pharmacological tools for hH3R visualization in different tissues.
Highlights
Histaminergic receptors belong to class A of membrane bound G-protein-coupled receptors (GPCRs)
All synthesized chalcone compounds could be used to visualize histamine H3 receptors (hH3R) proteins in stably transfected HEK-293 cells using confocal laser scanning fluorescence microscopy. These novel fluorescent ligands possess high potential to be used as pharmacological tools for hH3R visualization in different tissues
DESIGN OF NOVEL HUMAN HISTAMINE H3 LIGANDS Historically the first potent histamine H3 receptor ligands were derivatized from the endogenous ligand histamine
Summary
Histaminergic receptors belong to class A of membrane bound G-protein-coupled receptors (GPCRs). Attempts to design fluorescent human hH3R were established with motif structure elements of Sangers reagent, dansyl, NBD, cyanoisoindol, and tetramethylrhodamine groups (Amon et al, 2006, 2007; Cowart et al, 2006; Kuder et al, 2010) Most of these compounds showed high affinity at histamine H3 receptors (hH3R K i: 0.1–10 nM), but their fluorescence absorption and emission wavelengths were mainly between 300 and 500 nm. Tomecková et al (2004) reported on related cyclic chalcone analogs demonstrating biological effects on mitochondrial outer membrane via fluorescence microscopy These results motivated us to use chalcones as fluorescent element for labeling of histamine H3 receptor ligands to generate novel fluorescent pharmaceutical tools (Figure 1)
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