Currently patients with obstructive airways diseases have only one class of direct bronchodilators that are available for treatment (beta-agonists). These have many limitations, so there is an ongoing search for other direct bronchodilators.Bitter taste receptors (TAS2Rs) are expressed on multiple cell types and organ systems, including human airway smooth muscle (HASM). The use of TAS2R agonists can promote relaxation to constrictive stimuli and serve as a potential new treatment for obstructive lung diseases such as asthma and COPD. Currently, only one agonist was found for the TAS2R5 subtype, a dominant receptor on HASM, with reported low potency and efficacy.
Our investigators have screened for novel bronchodilators focusing on finding potent TAS2R5 agonists. Their lead compound showed the greatest potency (EC50 ~120 nM), amounting to >1000-fold improvement over other compounds, and displayed maximal efficacy. Since constricted airway smooth muscle is a main cause of airflow restriction in asthma and other obstructive lung diseases, these agonists can be used as therapeutics for these diseases.
Structure-activity relationships for TAS2R5 agonists.The previously verified TAS2R5 agonist 1,10 phenanthroline (blue data) displays low potency for stimulating [Ca2+]i in human airway smooth muscle (HASM) cells, and little relaxation (decrease in cell stiffness) of HASM as determined by magnetic twisting cytometry. Modifications at the convex face as shown in the 5,6-dione derivative (red data) increased potency in the [Ca2+]i response and caused marked relaxation of HASM.