Development of a Novel Benzodiazepine to Delineate Peripheral GABA-A Signaling Mechanisms in Visceral Pain Syndromes

BACKGROUND & AIMS: Visceral pain is a cardinal symptom of many disorders affecting the gut and other abdominal organs. Modulators of gamma-aminobutyric acid (GABA) such as benzodiazepines may attenuate such pain but the specific contribution of peripheral GABA-A receptors (GABRAs) remains unclear as current agonists have prominent central effects. METHODS: Using medicinal chemistry optimization of the benzodiazepine scaffold, we developed a novel and potent positive allosteric modulator (PAM), LI-633, with no significant central nervous system (CNS) penetration. RESULTS: of 70.4 nM. In vivo, LI-633 significantly attenuated visceral hypersensitivity and pain behavior in a rat model of irritable bowel syndrome (IBS) and functional dyspepsia (FD), indicating the presence of physiologically relevant concentrations of GABA in the colon and stomach. In the IBS model, administration of the drug also resulted in decreased excitability of colon-specific DRG neurons and significantly reduced the colonic afferent response to balloon distention as measured by recordings of neural activity in dorsal ganglia rootlets. CONCLUSIONS: These findings highlight the potential of targeting peripheral GABRAs for pain management in disorders associated with visceral hypersensitivity.