Pharmaceutical TAS2R14 Agonists Display Diverse Potency, Efficacy, and Binding-Site Sensitivity

Abstract

Bitter taste receptors (TAS2Rs) are G-protein coupled receptors that detect chemically diverse compounds, including many clinically used drugs. TAS2R14 is expressed in many extraoral tissues and is activated by hundreds of ligands, including pharmaceutical drugs. Recent cryo-EM structures revealed a previously unrecognized intracellular binding pocket in TAS2R14, raising new questions regarding ligand binding modes. Here, we investigated the activation of TAS2R14 by Tamoxifen, Carbimazole, and Lidocaine using cell-based assays measuring proximal G-protein recruitment (BRET2) and downstream signaling (IP-One). Tamoxifen and Carbimazole activated TAS2R14 with EC50 values in the low micromolar range, whereas Lidocaine required substantially higher concentrations. Targeted receptor mutations were used to evaluate the contribution of extracellular and intracellular binding regions to agonist activity. Carbimazole and Lidocaine showed greater dependence on the intracellular and extracellular positions, respectively, while Tamoxifen displayed assay-dependent, but overall modest sensitivity to the tested mutations. Thus, although existing drugs can activate TAS2R14 through distinct binding modes, TAS2R14-directed repurposing will depend on whether effective local receptor concentrations can be achieved through appropriate delivery strategies.