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Abstract
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 IP-One accumulation assay. In combination with a bioisosteric exchange of the carboxylic moiety by a tetrazole unit, a set of promising new TAS2R14 agonists was developed. The most potent ligand 28.1 (EC50 = 72 nM) revealed a six-fold higher potency than flufenamic acid and a maximum efficacy of 129%. Besides its unprecedented TAS2R14 activation, 28.1 revealed marked selectivity over a panel of 24 non-bitter taste human GPCRs.
Supplementary materials
Title
Discovery of 2-aminopyrimidines as potent agonists for the bitter taste receptor TAS2R14
Description
1) Figure S1. Screening of GPCR binding selectivity………………………………….…….……..... 2
2) Table S1. PAINS screening of target and reference compounds..…………...………................. 3
3) Table S2. Experimental conditions for GPCR screening…….…………………………………..... 8
4) Supplementary Text. Docking results………………………………………………………………. 9
5) Figure S2. Docking of ligands to the TAS2R14 model……………………………….…….……... 9
6) Supplementary Data. 1H and 13C NMR spectra of the target compounds…………...…………. 10
7) Supplementary Data. HPLC traces of the target compounds……………………………........... 46
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