Antitussive effects of the peripherally restricted GABA_B receptor agonist lesogaberan in guinea pigs: Comparison to baclofen and other GABA_B receptor-selective agonists

Background: Gastroesophageal reflux disease (GERD) is a common cause of chronic cough. Both acid and nonacid reflux is thought to play a role in the initiation of coughing and cough hypersensitivity. The GABA_B receptor agonist lesogaberan was developed as a peripherally restricted anti-reflux therapy that reduces the frequency of transient lower esophageal sphincter relaxations (TLESR; the major cause of reflux) in animals and in patients with GERD. GABA_B receptor agonists have also been shown to possess antitussive effects in patients and in animals independent of their effects on TLESR, suggesting that lesogaberan may be a promising treatment for chronic cough. Methods: We have assessed the direct antitussive effects of lesogaberan (AZD3355). The effects of other GABA_B receptor agonists were also determined. Coughing was evoked in awake guinea pigs using aerosol challenges with citric acid. Results: Lesogaberan dose-dependently inhibited citric acid evoked coughing in guinea pigs. Comparable effects of the GABA_B receptor agonists baclofen and 3-aminopropylphosphinic acid (3-APPiA) on cough were also observed. Baclofen produced obvious signs of sedation and respiratory depression. By contrast, both lesogaberan and 3-APPiA (both inactivated centrally by GABA transporters) were devoid of sedative effects and did not alter respiratory rate. Conclusions: Together, the data suggest that lesogaberan and related GABA_B receptor agonists may hold promise as safe and effective antitussive agents largely devoid of CNS side effects.