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

Histamine receptor 2 (HR_H2) activation in the stomach results in gastric acid secretion, and HR_H2 blockers are used for the treatment of peptidic ulcers and acid reflux. Over-the-counter HR_H2 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_H2 blocker scaffold to serve in the development of next-generation HR_H2 blockers, we developed an HR_H2-based sensor in yeast by linking human HR_H2 activation to cell luminescence. We used the HR_H2-based sensor to screen a 403-member anti-infection chemical library and identified three HR_H2 blockers, chlorquinaldol, chloroxine, and broxyquinoline, all sharing an 8-hydroxyquinoline scaffold, which is not found among known HR_H2 antagonists. Critically, we validate their HR_H2-blocking ability in mammalian cells. Molecular docking suggests that the HR_H2 blockers bind the histamine binding pocket and structure-activity data point toward these blockers acting as competitive antagonists. Chloroxine and broxyquinoline are antimicrobials that can be found in the gastrointestinal tract at concentrations that would block HR_H2, thus likely modulating gastric acid secretion. Taken together, this work demonstrates the utility of GPCR-based sensors for rapid drug discovery applications, identifies a novel HR_H2 blocker scaffold, and provides further evidence that antimicrobials not only target the human microbiota but also the human host.