Abstract

The concept of pharmacological efficacy has been much discussed recently with significant interest both in inverse agonists and in protean agonists (i.e., compounds with functional selectivity for different effector responses). Although first proposed in the mid-1990s, the pharmacological and therapeutic importance of these concepts is now receiving wider support. Two articles in recent issues of Molecular Pharmacology, Lane et al. (p. 1349, current issue) and Galandrin and Bouvier (Mol Pharmacol70:1575–1584, 2006), provide new mechanistic information on functionally selective ligands at the pharmacologically important D2 dopamine receptor and the β₁ and β₂ adrenergic receptors. Each article bridges a gap between recent biophysical studies showing distinct receptor conformations produced by different ligands and the increasing number of reports of discordant outputs by a single ligand to two effector readouts. The Lane et al. study clearly demonstrates G protein-specific actions of D₂ dopamine receptor ligands. These range from equivalent responses for Gα_o and Gα_i activation by norapomorphine and 7-hydroxy-2-dipropylaminotetralin to S-(–)-3-(3-hydroxyphenyl)-N-propylpiperidine, which is an agonist for Gα_o activation and an inverse agonist at Gα_i1 and Gα_i2. Likewise, Galandrin and Bouvier describe a two-dimensional Cartesian efficacy approach in which propranolol is an agonist for extracellular signal-regulated kinase activation, probably through β-arrestin, while functioning as an inverse agonist for adenylyl cyclase activation. Thus, these two important articles further solidify the concepts of functional selectivity and protean agonism and begin to define the first postreceptor step in actions of protean agonist ligands.