Asthma is a major health concern and millions of individuals are affected. Current asthma treatments, both chronic maintenance and acute rescue therapy, use β2-agonists and corticosteroids, both of which suffer from inadequate efficacy and safety issues. As a result, there is an unmet demand for more effective and safer treatments for asthma. Our previous studies demonstrated that airway smooth muscle (ASM) cells express GABAA receptors (GABAARs) of the α4 and α5 subunits and agonists of GABAAR can relax ASM acutely. Targeting the limited and overlapping α subunits with subtype selective GABAAR agonists would cause both ASM relaxation and suppression of inflammation without having any off-target CNS activity. Bz/GABAA ergic agents have been proven to be safe and have a long clinical safety record. As a result targeting Bz/GABAAR in the lung would be a novel and effective strategy in asthma management. Novel GABAAR positive allosteric modulators designed for α4/α6 subunit selectivity were synthesized using iterative computational analyses. Two compounds from our library, namely CMD-45 and XHe-III-74 have shown α4 subtype selectivity and serve as leads for designing novel drugs for treating asthma. Recent results in this area will be presented.

Novel strategy for the treatment of asthma by targeting the α4 subunit of GABAA receptors in airway smooth muscle

251st National Meeting (2016)

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