Insight into the Mode of Action of 8-Hydroxyquinoline-Based Blockers on the Histamine Receptor 2.

Histamine receptor 2 (HR) blockers are used to treat peptic ulcers and gastric reflux. Chlorquinaldol and chloroxine, which contain an 8-hydroxyquinoline (8HQ) core, have recently been identified as blocking HR. To gain insight into the mode of action of 8HQ-based blockers, here, we leverage an HR-based sensor in yeast to evaluate the role of key residues in the HR active site on histamine and 8HQ-based blocker binding.

Discovery of 8-Hydroxyquinoline as a Histamine Receptor 2 Blocker Scaffold.

Histamine receptor 2 (HR) activation in the stomach results in gastric acid secretion, and HR blockers are used for the treatment of peptidic ulcers and acid reflux. Over-the-counter HR blockers carry a five-membered aromatic heterocycle, with two of them additionally carrying a tertiary amine that decomposes to N-nitrosodimethylamine, a human carcinogen. To discover a novel HR blocker scaffold to serve in the development of next-generation HR blockers, we developed an HR-based sensor in yeast by linking human HR activation to cell luminescence.