Functional selectivity, ligand-directed trafficking, conformation-specific agonism: What’s in a name? Mol

In classical models of drug action, the primary event is binding of a ligand (L) to its receptor (R). The binding of an agonistic ligand (Box 1) to a membrane receptor leads to an intracellular effect, E, such that L + R n LR g E. The concentration dependence of the effect hinges on the binding affinity of L for R. The magnitude of the effect depends on the intrinsic efficacy of L. There are numerous examples showing that activation of a single receptor can lead to activation of multiple intracellular signaling events, such that: In traditional receptor theory, the relative degree of activation of E1 or E2 is the same for every agonist. For example, an agonist with half the efficacy of a reference agonist for E1 should also have half the efficacy of the reference agonist for E2. More recently, however, evidence from a variety of systems suggests that some ligands, acting at a single receptor, may preferentially activate E