TY - JOUR
T1 - Identification and Characterization of Novel Bronchodilator Agonists Acting at Human Airway Smooth Muscle Cell TAS2R5
AU - Kim, Donghwa
AU - An, Steven S.
AU - Lam, Hong
AU - Leahy, James W.
AU - Liggett, Stephen B.
N1 - Funding Information:
This work was funded by the National Institutes of Health (Grant HL114471 to S.B.L. and S.S.A.). S.S.A. was also supported by the New Jersey Alliance for Clinical and Translational Science (UL1TR0030117).
Publisher Copyright:
© 2020 American Chemical Society.
PY - 2020/12/11
Y1 - 2020/12/11
N2 - 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.
AB - 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.
KW - Ca
KW - G protein-coupled receptors
KW - airway smooth muscle
KW - bitter taste receptors
KW - magnetic twisting cytometry
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U2 - 10.1021/acsptsci.0c00127
DO - 10.1021/acsptsci.0c00127
M3 - Article
AN - SCOPUS:85097081017
VL - 3
SP - 1069
EP - 1075
JO - ACS Pharmacology and Translational Science
JF - ACS Pharmacology and Translational Science
SN - 2575-9108
IS - 6
ER -