Agonists and Antagonists of the broadly tuned hTAS2R-receptors

TAS2R receptors (TAS2Rs) are responsible for detecting bitter taste and, with a few remarkable exceptions, are broadly tuned to recognize a diverse range of compounds. Their ectopic expression suggests additional roles beyond sensory perception, potentially offering health benefits. However, no universal bitter chemotype has yet emerged to guide the design of specific ligands, with most available data on TAS2Rs focusing on dietary phytochemicals. The presence of a lactone ring in structurally distinct sesquiterpene and diterpene activators of TAS2R46 provided a rationale for investigating the affinity of these ligands across the full spectrum of human bitter receptors. This study assessed how the lactone chemotype interacts within the human bitter receptor landscape, revealing a complex activation pattern. Results indicate that the lactone bitter chemotype is inherently promiscuous, with all tested compounds capable of binding to at least 11 TAS2Rs. Nevertheless, modulation by the surrounding molecular framework was evident. For instance, TAS2R8 exhibited a preference for hydroxylated sesquiterpenes of the germacrane type, while TAS2R14 favored cis-eudesmanolides. Collectively, these findings validate the lactone motif as a key bitter-inducing element beyond TAS2R46, establishing the lactone “pharmacophore” as a crucial structural feature for bitter receptor interaction. This insight underscores its potential for the rational design of novel bitter receptor ligands.