Protean agonism at histamine H3 receptors in vitro and in vivo

摘要: G protein-coupled receptors (GPCRs) are allosteric proteins that adopt inactive (R) and active (R*) conformations in equilibrium. R* is promoted by agonists or occurs spontaneously, leading to constitutive activity of the receptor. Conversely, inverse promote R decrease activity. The existence another pharmacological entity, referred as “protean” (after Proteus, Greek god who could change shape), was assumed on theoretical grounds. It predicted from a same ligand this class act either an agonist at GPCR. Here, we show proxyfan, high-affinity histamine H3-receptor ligand, acts protean recombinant H3 expressed Chinese hamster ovary cells. In support physiological relevance process, proxyfan also behaves native known display On neurochemical behavioral responses rodents cats, displays spectrum ranging full agonism agonism. Thus, demonstrates ligand-directed states LR* different from, competing with, constitutively GPCRs, defines entity with important therapeutic implications.