Department of Chemistry and Pharmacy, Medicinal Chemistry, Friedrich-Alexander-Universität Erlangen-Nürnberg, Nikolaus-Fiebiger-Str. 10, Erlangen 91058, Germany.
The Robert H. Smith Faculty of Agriculture, Food and Environment, Institute of Biochemistry, Food Science and Nutrition, The Hebrew University, Rehovot 7610001, Israel.
J Med Chem. 2023 Mar 9;66(5):3499-3521. doi: 10.1021/acs.jmedchem.2c01997. Epub 2023 Feb 27.
The bitter taste receptor TAS2R14 is a G protein-coupled receptor that is found on the tongue as well as in the human airway smooth muscle and other extraoral tissues. Because its activation causes bronchodilatation, TAS2R14 is a potential target for the treatment of asthma or chronic obstructive pulmonary disease. Structural variations of flufenamic acid, a nonsteroidal anti-inflammatory drug, led us to 2-aminopyridines showing considerable efficacy and potency in an IPaccumulation assay. In combination with an exchange of the carboxylic moiety by a tetrazole unit, a set of promising new TAS2R14 agonists was developed. The most potent ligand (EC = 72 nM) revealed a six-fold higher potency than flufenamic acid and a maximum efficacy of 129%. Besides its unprecedented TAS2R14 activation, revealed marked selectivity over a panel of 24 non-bitter taste human G protein-coupled receptors.
苦味受体 TAS2R14 是一种 G 蛋白偶联受体，不仅存在于舌头上，还存在于人类气道平滑肌和其他口腔外组织中。由于其激活可导致支气管扩张，因此 TAS2R14 是治疗哮喘或慢性阻塞性肺疾病的潜在靶点。非甾体抗炎药氟芬那酸的结构变异导致我们发现 2-氨基吡啶在 IP 积累测定中具有相当的疗效和效力。通过用四唑单元替换羧酸部分，开发了一组有前途的新型 TAS2R14 激动剂。最有效的配体（EC = 72 nM）的效力比氟芬那酸高六倍，最大效力为 129%。除了具有前所未有的 TAS2R14 激活作用外，还显示出对 24 个人类非苦味味觉 G 蛋白偶联受体的显著选择性。
