Presented at the 2012 AAPM Annual Meeting « Back

A G Protein-Biased Mu-Opioid Receptor Ligand Elicits Potent Analgesia but Reduced Constipation and Respiratory Depression Compared to Morphine in Rodents

Jonathan D. Violin, PhD, jviolin@trevenainc.com¹, David G. Soergel, MD¹, Christopher J. LaBuda, PhD¹, Scott M. DeWire, PhD¹, Dennis Yamashita, PhD², Michael W. Lark, PhD¹, (1) Trevena Inc., King Of Prussia, Pennsylvania, (2) American Chemical Society, King Of Prussia, Pennsylvania

Introduction: Morphine elicits analgesia via the mu-opioid receptor, but also elicits severe and treatment-limiting adverse effects, including constipation and respiratory depression, through the same receptors. Published evidence from knockout mice indicates that these effects are mediated by distinct intracellular signaling pathways downstream of the mu-opioid receptor: morphine exerts increased analgesia but decreased constipation and respiratory depression in beta-arrestin2 knockout mice (1, 2). Approach: We sought “biased ligands,” which selectively engage subsets of receptor signals (3), to harness these findings to discover novel, improved opioid analgesics. Results: This effort led to the discovery of TRV002, a novel, potent, and selective G protein-biased mu-opioid receptor ligand. TRV002 robustly engages G protein coupling with efficacy and potency comparable to morphine, but displays dramatically reduced beta-arrestin coupling. In mice and rats, TRV002 is a potent analgesic, but displays marked improvement in constipation and respiratory depression when compared to morphine. Conclusion: The improved therapeutic index of TRV002 could allow safer, more effective pain management by removing key barriers to effective opioid therapy. References: 1)Bohn LM, Lefkowitz RJ, Gainetdinov RR, Peppel K, Caron MG, Lin FT. Enhanced morphine analgesia in mice lacking beta-arrestin 2. Science 1999; 286(5449): 2495-2498 2)Raehal KM, Walker JK, Bohn LM. Morphine side effects in beta-arrestin 2 knockout mice. J Pharmacol Exp Ther. 2005; 314(3): 1195-1201 3)Violin JD, Lefkowitz RJ. Beta-arrestin-biased ligands at seven-transmembrane receptors. Trends Pharmacol Sci. 2007; 28(8): 416-422

Funding: Supported by Trevena Inc., King of Prussia, PA