Identification and Characterization of Novel Bronchodilator Agonists Acting at Human Airway Smooth Muscle Cell TAS2R5,ACS Pharmacology & Translational Science

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Identification and Characterization of Novel Bronchodilator Agonists Acting at Human Airway Smooth Muscle Cell TAS2R5
ACS Pharmacology & Translational Science ( IF 4.9 ) Pub Date : 2020-11-05 , DOI: 10.1021/acsptsci.0c00127
Donghwa Kim ₁ , Steven S An ₂ , Hong Lam ₂ , James W Leahy _{3,

4} , Stephen B Liggett _{1,

5}

Affiliation

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.

中文翻译：

作用于人气道平滑肌细胞 TAS2R5 的新型支气管扩张剂激动剂的鉴定和表征

苦味受体 (TAS2R) 被认为在多种细胞类型和器官上表达，包括人气道平滑肌 (HASM) 细胞，其中的激动剂可促进对收缩刺激的显着放松。因此，HASM TAS2Rs 已成为治疗哮喘和其他阻塞性肺病的新型支气管扩张剂。TAS2R5 亚型是 HASM 的主要受体，几乎没有已知的激动剂，据报道所有这些都具有低效力和功效。我们通过测量 [Ca ²⁺ ] _i筛选了多种化合物在 HASM 中释放（受体-G 蛋白偶联的结果）以建立结构-活性关系并获得 TAS2R5 的有效激动剂。使用磁扭曲细胞计数的 HASM 生理学研究证实了先导化合物的弛豫效应。1,10-Phenanthroline-5,6-dione 具有最大的效力 (EC ₅₀ ≈ 120 nM)，与其他化合物相比提高了 >1000 倍，并显示出最大的功效。这些研究揭示了针对气道 TAS2R5 的潜在一流支气管扩张剂的有利效力和功效的关键结构要求。

更新日期：2020-12-12

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