Biased Ligands. Better Drugs.

History of GPCR Biased Ligands

The capacity of a receptor to signal through both G proteins and β-arrestins was discovered in the late 1990s and early 2000s(1) in the laboratory of Robert Lefkowitz M.D. at Duke University, using the angiotensin II receptor as a model. We now know that β-arrestins can activate a broad set of intracellular signaling molecules for numerous GPCRs(2). Later work demonstrated that G protein and β-arrestin pathways are distinct and can be pharmacologically modulated independently with "biased ligands"(3). In the mid 2000s, a handful of biased ligands were discovered that specifically targeted G protein or β-arrestin signaling, and the idea of biased GPCR signaling emerged as a new theme in receptor biology(4,5). With a new appreciation of the diversity of signals that can be elicited by GPCR ligands, Dr. Lefkowitz and his colleague Howard Rockman M.D., also at Duke University, began to consider the possibility that biased ligands had the potential to uniquely modify GPCR-mediated pharmacology to deliver new and differentiated medicines. Dr. Lefkowitz was awarded the 2012 Nobel Prize for Chemistry for his studies of GPCRs. His Nobel Lecture, including discussion of biased ligands, can be viewed on the Nobel Prize Website.

Trevena was founded to harness the promise of biased ligands, with Drs. Lefkowitz and Rockman as academic co-founders. The company has successfully demonstrated that biased ligands can be discovered and optimized for a number of distinct GPCRs. Furthermore, these biased ligands exhibit a unique spectrum of pharmacological responses.(6,7) This approach has the potential to deliver the next generation of GPCR-targeted therapeutics to meet significant unmet patient needs. Trevena has discovered multiple biased ligands now in development as potential first-in-class and best-in-class medicines to treat serious unmet medical needs.


1. Lefkowitz, R.J., and Shenoy, S.K. 2005. Transduction of receptor signals by β-arrestins. Science 308:512-517.
2. DeWire, S.M., Ahn, S., Lefkowitz, R.J., and Shenoy, S.K. 2007. β-arrestins and cell signaling. Annu Rev Physiol 69:483-510.
3. Wei, H., Ahn, S., Shenoy, S.K., Karnik, S.S., Hunyady, L., Luttrell, L.M., and Lefkowitz, R.J. 2003. Independent β-arrestin 2 and G protein-mediated pathways for angiotensin II activation of extracellular signal-regulated kinases 1 and 2. Proc Natl Acad Sci U S A 100:10782-10787.
4. Violin, J.D., and Lefkowitz, R.J. 2007. β-arrestin-biased ligands at seven-transmembrane receptors. Trends Pharmacol Sci 28:416-422.
5. DeWire S.M., and Violin, J.D. 2011. Biased ligands for better cardiovascular drugs: dissecting G protein-coupled receptor pharmacology. Circ Res. Jul 8;109(2):205-16.
6. Violin J.D., DeWire S.M., Yamashita D., Rominger D.H., Nguyen L., Schiller K., Whalen E.J., Gowen M., Lark M.W. 2010. Selectively engaging β-arrestins at the angiotensin II type 1 receptor reduces blood pressure and increases cardiac performance. J Pharmacol Exp Ther. Dec;335(3):572-9.
7. DeWire SM, Yamashita DS, Rominger DH, Liu G, Cowan CL, Graczyk TM, Chen XT, Pitis PM, Gotchev D, Yuan C, Koblish M, Lark MW, Violin JD. 2013. A G protein-biased ligand at the μ-opioid receptor is potently analgesic with reduced gastrointestinal and respiratory dysfunction compared with morphine. J Pharmacol Exp Ther. 2013 Mar;344(3):708-17.

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