Dietary Terpenoid Lactones are Promiscuous Agonists of Bitter Taste Receptors (TAS2Rs)

The observation that a lactone ring is present in structurally distinct natural classes of sesquiterpenoid and diterpenoid activators of bitter receptor TAS2R46 provided a rationale to investigate the potency of a set of these natural products across the whole range of human bitter receptors. TAS2Rs are responsible for detecting bitter taste and, with some exceptions, are broadly tuned to recognize a wide range of compounds. The ectopical expression of TAS2Rs suggests additional role(s) beyond sensory perception, but no general bitter chemotype has emerged so far to inspire the design of a specific agonist. From our study, a complex pattern of TAS2Rs activation emerged, showing that the lactone pharmacophore is not specific for TAS2R46 but, depending on its framework, can also activate different sets of taste receptors. Taken together, our results expand the role of the lactone ring as a bitter chemotype and qualify dietary terpenoid lactones as excellent lead for the design of specific bitter receptors modulators.