Drugs in the PipelineG Protein–coupled Receptor Biased AgonismHodavance, Sima Y. MD; Gareri, Clarice PhD; Torok, Rachel D. MD; Rockman, Howard A. MDAuthor Information Departments of *Medicine; and †Pediatrics, Duke University Medical Center, Durham, NC. Reprints: Howard A. Rockman, MD, Department of Medicine, Duke University Medical Center, DUMC 3104, 226 CARL Building, Research Drive, Durham, NC 27710 (e-mail: [email protected]). National Institutes of Health grants HL56687 and HL75443 to H. A. Rockman; National Institutes of Health/National Institute of Child Health and Human Development grant HD000850-30 to R. D. Torok. H. A. Rockman is a scientific cofounder for Trevena Inc, a company that is developing G protein–coupled receptor-targeted drugs. The other authors report no conflicts of interest. S. Y. Hodavance and C. Gareri have contributed equally. Received November 16, 2015 Accepted December 12, 2015 Journal of Cardiovascular Pharmacology: March 2016 - Volume 67 - Issue 3 - p 193-202 doi: 10.1097/FJC.0000000000000356 Buy Metrics Abstract G protein–coupled receptors are the largest family of targets for current therapeutics. The classic model of their activation was binary, where agonist binding induced an active conformation and subsequent downstream signaling. Subsequently, the revised concept of biased agonism emerged, where different ligands at the same G protein–coupled receptor selectively activate one downstream pathway versus another. Advances in understanding the mechanism of biased agonism have led to the development of novel ligands, which have the potential for improved therapeutic and safety profiles. In this review, we summarize the theory and most recent breakthroughs in understanding biased signaling, examine recent laboratory investigations concerning biased ligands across different organ systems, and discuss the promising clinical applications of biased agonism. Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.