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

We have assessed the direct antitussive effects of lesogaberan (AZD3355). The effects of other GABAB receptor agonists were also determined. Coughing was evoked in awake guinea pigs using aerosol challenges with citric acid.Lesogaberan dose-dependently inhibited citric acid evoked coughing in guinea pigs. Comparable effects of the GABAB 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.Together, the data suggest that lesogaberan and related GABAB receptor agonists may hold promise as safe and effective antitussive agents largely devoid of CNS side effects.Cough is one of the most commonly reported symptoms amongst patients seeking medical advice. Acute cough is triggered primarily by viral infections, while the most common causes of chronic cough are asthma, upper airway inflammatory disorders, and gastroesophageal reflux disease (GERD). Therapeutics used specifically for the treatment of cough are either minimally effective or have unwanted side effects that limit their utility. In patients with chronic cough, treatment of their underlying disease can improve patient quality of life and reduce coughing. But for many patients with chronic, troublesome cough, even after aggressive medical treatment of their underlying illnesses, cough can remain a significant health problem that adversely impacts quality of life. New and more effective and selective treatments for cough thus represent an unmet need in respiratory medicine [1,2].Agonists of the metabotropic GABAB receptor such as baclofen have been evaluated for their utility in targeting a number of peripheral disorders thought to involve aberrant reflexes and sensations including pain, overactive bladder, hiccups, tetanus/spasticity, and hea