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

[Image: see text] 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.