Identification and Characterization of Novel Bronchodilator Agonists Acting at Human Airway Smooth Muscle Cell TAS2R5

Donghwa Kim, Steven S. An, Hong Lam, James W. Leahy, Stephen B. Liggett

Research output: Contribution to journalArticlepeer-review

Abstract

Bitter taste receptors (TAS2Rs) are recognized as being expressed on multiple cell types and organs, including human airway smooth muscle (HASM) cells, where agonists promote significant relaxation to constrictive stimuli. Thus, the HASM TAS2Rs have been targeted as novel bronchodilators for the treatment of asthma and other obstructive lung diseases. The TAS2R5 subtype, a dominant receptor on HASM, has few known agonists, all with reported low potency and efficacy. We screened multiple compounds by measuring [Ca2+]i release in HASM (a consequence of receptor-G protein coupling) to establish structure-activity relationships and arrive at a potent agonist for TAS2R5. HASM physiological studies using magnetic twisting cytometry confirmed the relaxation effects of lead compounds. 1,10-Phenanthroline-5,6-dione had the greatest potency (EC50 ≈ 120 nM), amounting to a >1000-fold improvement over the other compounds, and displayed maximal efficacy. These studies revealed critical structural requirements for favorable potencies and efficacies for a potential first-in-class bronchodilator targeting TAS2R5 of the airway.

Original languageEnglish (US)
Pages (from-to)1069-1075
Number of pages7
JournalACS Pharmacology and Translational Science
Volume3
Issue number6
DOIs
StatePublished - Dec 11 2020

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmacology (medical)

Keywords

  • Ca
  • G protein-coupled receptors
  • airway smooth muscle
  • bitter taste receptors
  • magnetic twisting cytometry

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