L13
A New Pharmacological Approach for Asthma through Tissue-Specific Modulation of the GABA(A) Receptor
Sunday, March 6, 2016
South Exhibit Hall H (Convention Center)
Leggy A. Arnold, PhD, Gloria S. Forkuo, PhD, Amanda N. Nieman, Olivia B. Yu, Margaret L. Guthrie, Nina Y. Yuan, Revathi Kodali, Rajwana Jahan, Charles W Emala, James M. Cook, PhD, Douglas C. Stafford, PhD, Mitchell H. Grayson, MD FAAAAI
Rationale:

This study addresses the unmet need for an oral, safe, non-steroidal asthma treatment by targeting GABAA receptors (GABAAR) in lung tissues. The hypothesis is that GABAARs in inflammatory and airway smooth muscle (ASM) cell can be targeted by subtype-selective GABAAR agonists to tissue-selectively induce immunosuppression and ASM relaxation.

 Methods:

A drug discovery approach identified GABAAR targets in lung cells by immunodetection, subtype selectivity by electrophysiology, preclinical characterization of active ligands using microsomes, S9, and blood plasma stability assays. Pharmacokinetic studies in mice are applied to identify in vivo stability and distribution. Murine pharmacodynamic models are used to quantify sensorimotor effects (rotarod), disease specific airway hyperresponsiveness, airway mucus production, and airway eosinophilia. Subtype-selective GABAAR ligands were evaluated for immune modulation using in vitro T-cell assays and ASM muscle relaxation with isolated ASM.

 Results:

The α4 subtype-selective GABAAR ligand XHE-III-74EE showed high stability in vitro but a limited half-life in vivo due to rapid metabolism and clearance. Chronic administration of 20 mg/kg XHE-III-74EE successfully reduced airway hyperresponsiveness without inducing adverse CNS effects. Mucus hypersecretion was reduced for chronic and acute treatment. Similar results were observed for metabolite XHE-III-74A that exhibits α4 GABAAR subtype selectivity. XHE-III-74A significantly reduced eosinophilia, which is consistent with antiinflammatory suppressive effects in activated T-cells as measured by intracellular calcium release and IL-2 production. Both compounds were able to induce ASM muscle relaxation.

 Conclusions:

α4-Selective GABAAR agonists have a great potential as novel drug candidates for asthma to alleviate symptoms of airway hyperresponsiveness mediated by ASM constriction, hypereosinophilia, inflammation, and mucus overproduction.