Functional selectivity and biased receptor signaling

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 336; no. 2; p. 296
• Main Author: Kenakin, Terry
• Format: Journal Article
• Language: English
• Published: United States 01-02-2011
• Subjects: Animals; Arrestins - physiology; beta-Arrestins; Drug Discovery; Humans; Ligands; Protein Conformation; Receptors, Drug - agonists; Receptors, Drug - chemistry; Receptors, Drug - physiology; Signal Transduction - physiology
• ISSN: 1521-0103
• DOI: 10.1124/jpet.110.173948

With the emergence of information describing functional selectivity and biased agonists and antagonists has come a lack of confidence in "one size fits all" assays for detection of agonism. Seven-transmembrane receptors are pleiotropic with respect to the signaling protein to which they couple in a cell, and many conformations of the receptor can be formed; this leads to systems where ligands can stabilize unique conformations that go on to selectively activate signaling pathways. Thus, such "biased" ligands can produce cell-specific agonism that may require targeted assays to detect and quantify. It also predicts that ligands can have many different efficacies for the many behaviors that the receptor can exhibit (referred to as "pluridimensional efficacy"), leading to a breakdown in the common classifications of agonist and antagonist. This all poses unique challenges to the pharmacologic nomenclature of drugs, the detection and optimization of new drugs, and the association of phenotypic clinical profiles with pharmacological properties of drugs.