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

Area of Science:

• Pharmacology
• Drug Discovery
• Biochemistry

Background:

• Histamine H2 receptor (H2R) activation stimulates gastric acid secretion, making H2R blockers crucial for treating peptic ulcers and acid reflux.
• Current over-the-counter H2R blockers may contain impurities that form carcinogens, necessitating the development of novel, safer alternatives.
• The identification of new H2R antagonist scaffolds is essential for next-generation therapeutics.

Purpose of the Study:

• To discover a novel scaffold for histamine H2 receptor (H2R) blockers.
• To develop a high-throughput screening method for identifying H2R antagonists.
• To validate the efficacy and mechanism of newly identified H2R blockers.

Main Methods:

• Development of a yeast-based sensor linking human H2R activation to cell luminescence.
• Screening of a 403-member anti-infection chemical library using the H2R sensor.
• Validation of H2R-blocking activity in mammalian cells and molecular docking studies.

Main Results:

• Identification of three H2R blockers: chlorquinaldol, chloroxine, and broxyquinoline, all featuring an 8-hydroxyquinoline scaffold.
• The identified compounds bind to the histamine binding pocket of H2R, acting as competitive antagonists.
• Chloroxine and broxyquinoline, existing antimicrobials, exhibit H2R-blocking concentrations in the gastrointestinal tract.

Conclusions:

• The study demonstrates the utility of GPCR-based sensors for rapid drug discovery.
• A novel 8-hydroxyquinoline scaffold for H2R blockers has been identified.
• Antimicrobials may possess dual activity, targeting both microbiota and host receptors like H2R.