Bartole, Edith and Graetz, Lukas and Littmann, Timo and Wifling, David and Seibel, Ulla and Buschauer, Armin and Bernhardt, Guenther (2020) UR-DEBa242: A Py-5-Labeled Fluorescent Multipurpose Probe for Investigations on the Histamine H-3 and H-4 Receptors. JOURNAL OF MEDICINAL CHEMISTRY, 63 (10). pp. 5297-5311. ISSN 0022-2623, 1520-4804
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Comprehensively characterized fluorescent probes for the histamine H-3 receptor (H3R) and especially for the H4R orthologs [e.g., human (h) and mouse (m)] are highly needed as versatile complementary tools to radioligands. In view of fluorescent probes for BRET-based binding studies and for localizing the H4R in live cells, we synthesized and biologically characterized Py-5-labeled histamine derivatives. The most notable compound was UR-DEBa242 (26, 1-[4-(1H-Imidazol-4-yl)butyl]-4-{(1E,3E)-4-[4-(dimethylamino)phenyl]buta-1,3-dienyl}-2,6-dimethylpyridinium hydrotrifluoroacetate trifluoroacetate), acting as a partial agonist at the hH(3)R [pEC(50) (reporter gene) 8.77] and as an inverse agonist/antagonist at the h/mH(4)Rs [pIC(50) (reporter gene) 8.76/7.08; pIC(50)/pK(b) (beta-arrestin2) 7.81/7.30]. In confocal microscopy, 26 proved suitable for hH(4)R localization and trafficking studies in live cells. BRET-based binding at the NLuc-hH(3,4)Rs/mH(4)R [pK(d) 8.78/7.75/7.18, comparable to binding constants from radioligand binding/flow cytometry; fast association/dissociation (similar to 2 min)] revealed 26 as a useful molecular tool to determine hH(3,4)Rs/mH(4)R binding affinities of ligands binding to these receptors.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | PHARMACOLOGICAL CHARACTERIZATION; LIGAND-BINDING; 1ST POTENT; H-2-RECEPTOR; H-4-RECEPTOR; ANTAGONISTS; CLONING; |
| Subjects: | 600 Technology > 615 Pharmacy |
| Divisions: | Chemistry and Pharmacy > Institute of Pharmacy Chemistry and Pharmacy > Institute of Pharmacy > Alumni or Retired Professors > Pharmaceutical/Medicinal Chemistry II (Prof. Buschauer) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 23 Mar 2021 09:27 |
| Last Modified: | 23 Mar 2021 09:27 |
| URI: | https://pred.uni-regensburg.de/id/eprint/44515 |
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