Elucidating GPCR Functional Selectivity: Novel Opportunities for Drug Development

Elucidating GPCR Functional Selectivity: Novel Opportunities for Drug Development

Tuesday, September 30, 2014

The New York Academy of Sciences

Presented By

 

G protein-coupled receptors (GPCRs), the single largest class of druggable targets in therapeutic drug discovery, signal via canonical pathways involving heterotrimeric G proteins, and also via G protein–independent interactions with other signaling proteins, including β-arrestins, a process known as functional selectivity. Discovering ligands with the desired signaling bias at GPCRs will yield molecules with novel activities, and could lead to significantly improved therapeutics by enabling beneficial efficacy while reducing undesirable adverse effects. This symposium examines perspectives from academic and industrial scientists, highlighting basic and translational research. Researchers will discuss molecular and structural mechanisms underlying ligand bias and demonstrate how they quantify, design and develop functionally selective GPCR ligands for potential use in cardiovascular and central nervous system diseases.

*Reception to follow.

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The Biochemical Pharmacology Discussion Group is proudly supported by



  • Merck
  • WilmerHale

Mission Partner support for the Frontiers of Science program provided by Pfizer

Agenda

* Presentation titles and times are subject to change.


Tuesday September 30, 2014

8:30 AM

Registration and Continental Breakfast

9:00 AM

Welcome and Introduction
Brooke Grindlinger, PhD, The New York Academy of Sciences

9:10 AM

The Paradigm of GPCR Functional Selectivity and Implications for Drug Development
John A. Allen, PhD, Pfizer

9:30 AM

Beyond Signaling Bias
Terry Kenakin, PhD, University of North Carolina School of Medicine

10:10 AM

How Much Bias do we Need? Elucidating Ligand-Directed Signaling in vivo
Laura Bohn, PhD, The Scripps Research Institute - Florida

10:50 AM

Networking coffee break

11:20 AM

Glycosylation of Proteas-activated Receptor-1 Regulates G Protein Signaling Pathway Bias
JoAnn Trejo, PhD, University of California, San Diego

12:00 PM

Extending the Bitopic Ligand Paradigm: A Novel Mechanism of Allostery in a G Protein-coupled Receptor Dimer
Jonathan A. Javitch, MD, PhD, Columbia University and New York State Psychiatric Institute

12:40 PM

Networking lunch break

1:40 PM

Keynote Presentation
A Brief History of β-arrestins: From Birth to Bias
Robert J. Lefkowitz, MD, Duke University Medical Center

2:30 PM

Structural Features Responsible for GPCR Functional Selectivity
Bryan L. Roth, MD, PhD, University of North Carolina School of Medicine

3:10 PM

Networking coffee break

3:40 PM

Implications for CPCR Functional Selectivity/Biased Signaling in the Actions of Dopamine
Marc G. Caron, PhD, Duke University Medical Center

4:20 PM

First Clinical Evidence That Biased Ligands Improve GPCR Therapeutic Pharmacology
Jonathan D. Violin, PhD, Trevena Inc

5:00 PM

Closing Remarks
Mercedes Beyna, MS

Networking reception

6:00 PM

Close

Speakers

Organizers

John A. Allen, PhD

Pfizer

John Allen earned a PhD in Physiology & Biophysics from the University of Illinois College of Medicine studying cell and molecular mechanisms regulating Gs/adenylyl cyclase/cAMP signaling followed by post-doctoral training at the University of North Carolina School of Medicine researching mechanisms of antipsychotic drug action and the neuropharmacology of serotonin and dopamine receptors. In 2011 John joined Pfizer Neuroscience where his research is aimed at identifying and advancing new therapeutic targets to treat neurological diseases including the profiling of GPCRs for preclinical drug development. His recent work has studied functional selectivity at the dopamine receptors and determined structural mechanisms enabling ligand bias. John is a member of the Society for Neuroscience and ASPET and has received research awards including a Young Investigator Award from the American College of Neuropsychopharmacology and a NARSAD Young Investigator Award.

Mercedes Beyna, MS

Pfizer

Mercedes Beyna is a scientist in the Neuroscience Research Unit at Pfizer. Her research focuses on target identification and assay development in the areas of psychiatric as well as neurodegenerative disorders. Captivated by neuroscience, she has worked in the field for over 10 years, in both academic and industrial laboratory settings. Before joining pharmaceutical R&D, Mercedes held lab manager and senior lab technician positions at New York University (NYU). Mercedes attended Binghamton University, earning her undergraduate degree in Biology, and subsequently received her Master's Degree in Biology from NYU. As the Pfizer lead in the Biochemical Pharmacology Discussion Group at the New York Academy of Sciences, she enjoys developing interesting and educational symposia.

Bryan L. Roth, MD, PhD

University of North Carolina School of Medicine

Bryan Roth MD, PhD, is the Michael Hooker Distinguished Professor of Pharmacology at UNC Chapel Hill Medical School. Dr. Roth received postdoctoral training in molecular pharmacology at NIH and his psychiatry training at Stanford. His research interests include chemical and synthetic biology particularly as they apply to G-protein coupled receptors. He has published nearly 400 papers and given 100's of invited talks. Dr. Roth serves on the boards of many pharmacology and chemistry journals and, in addition, is currently the Deputy Editor of the Journal of Clinical Investigation. Dr. Roth also directs the National Institute of Mental Health's small molecule screening program--now in its 16th year. Over the past 5 years, this program (NIMH-PDSP) has facilitated work on more than 500 projects and contributed to more than 500 publications and patents assisting investigators world-wide.

Jennifer Henry, PhD

The New York Academy of Sciences

Keynote Speaker

Robert J. Lefkowitz, MD

Duke University Medical Center

Robert J. Lefkowitz, MD is James B. Duke Professor of Medicine and Professor of Biochemistry at the Duke University Medical Center. He has been an Investigator of the Howard Hughes Medical Institute since 1976. He has received numerous awards and honors for his research, including the National Medal of Science, the Shaw Prize, the Albany Prize, and the 2012 Nobel Prize in Chemistry. He was elected to the USA National Academy of Sciences in 1988; the American Academy of Arts and Sciences in 1983, and the Institute of Medicine in 1994. He is best known for his studies of G protein coupled receptors, a field which he has pioneered for more than 45 years.

Speakers

John A. Allen, PhD

Pfizer

John Allen earned a PhD in Physiology & Biophysics from the University of Illinois College of Medicine studying cell and molecular mechanisms regulating Gs/adenylyl cyclase/cAMP signaling followed by post-doctoral training at the University of North Carolina School of Medicine researching mechanisms of antipsychotic drug action and the neuropharmacology of serotonin and dopamine receptors. In 2011 John joined Pfizer Neuroscience where his research is aimed at identifying and advancing new therapeutic targets to treat neurological diseases including the profiling of GPCRs for preclinical drug development. His recent work has studied functional selectivity at the dopamine receptors and determined structural mechanisms enabling ligand bias. John is a member of the Society for Neuroscience and ASPET and has received research awards including a Young Investigator Award from the American College of Neuropsychopharmacology and a NARSAD Young Investigator Award.

Laura Bohn, PhD

The Scripps Research Institute - Florida

Laura Bohn, PhD is a professor of Molecular Therapeutics and Neuroscience at The Scripps Research Institute. She is an internationally recognized researcher investigating the function of G protein-coupled receptors which are critical to how patients respond to various therapeutics, including the opioid analgesics and antipsychotic agents. Dr. Bohn earned Bachelors degrees in both Chemistry and Biochemistry from Virginia Tech and then went on to get her PhD in Biochemistry and Molecular Biology from St. Louis School of Medicine. She received post-doctoral training in the Howard Hughes Medical Institute at the Duke University Medical Center in the laboratory of Dr. Marc Caron. Dr. Bohn joined the faculty and achieved tenure at The Ohio State University College of Medicine in the Departments of Pharmacology and Psychiatry. She joined Scripps Florida in March, 2009, in the departments of Molecular Therapeutics and Neuroscience where she is pursuing new therapies for the treatment of pain. In recognition of her achievements, she has received the Women in Neuroscience/Society for Neuroscience Career Development Award, was awarded the 2009 Joseph Cochin Young Investigator Award presented by the College of Drug Dependence and received the John J. Abel Award in Pharmacology from the American Society for Pharmacological and Experimental Therapeutics and Pfizer. In the past 5 years, Dr. Bohn has served as a consultant to Trevena Inc., Purdue Pharma, LP, and Mencuro Therapeutics, Inc.; she currently collaborates with Eli Lilly & Company. Her research program at The Scripps Research Institute is funded by the National Institutes on Drug Abuse.

Marc G. Caron, PhD

Duke University Medical Center

Marc G. Caron holds a PhD from the University of Miami. He is a James B. Duke Professor of Cell Biology at Duke University Medical Center. His long-standing research interests have been in the mechanisms and regulation of G protein-coupled receptors and on the mechanisms of neurotransmission as controlled by neurotransmitter transporters. His recent efforts have been centered on using genetic approaches to develop animal models of abnormal neurobiological function including disorders associated with aberrant serotonergic, dopaminergic and reward mechanisms.

Jonathan A. Javitch, MD, PhD

Columbia University and New York State Psychiatric Institute

Jonathan A. Javitch obtained his BS and MS in Biological Sciences at Stanford University. He completed the joint MD-PhD program at the Johns Hopkins University School of Medicine where as a graduate student with Solomon Snyder he demonstrated that a key step in the neurotoxicity of MPTP is the uptake of its metabolite MPP+ by the dopamine transporter. Dr. Javitch completed a medical internship and psychiatric residency at the Columbia Presbyterian Hospital and the New York State Psychiatric Institute. He did postdoctoral work on the structure of dopamine receptors with Dr. Arthur Karlin at Columbia University. Dr. Javitch is currently the Lieber Professor of Experimental Therapeutics in Psychiatry and Professor of Pharmacology in the Center for Molecular Recognition and in Physiology and Cellular Biophysics at the Columbia University College of Physicians and Surgeons, Director of the Lieber Center for Schizophrenia Research and Treatment, and Chief of the Division of Molecular Therapeutics at the New York State Psychiatric Institute. His research focuses on the structure, function and regulation of G protein-coupled receptors and neurotransmitter transporters.

Terry Kenakin, PhD

University of North Carolina School of Medicine

Beginning his career as a synthetic chemist, Terry Kenakin received a PhD in Pharmacology at the University of Alberta, Edmonton Canada. After a post-doctoral Fellowship at University College London, U.K., he joined Burroughs-Wellcome as an associate Scientist. From there he continued working in drug discovery at Glaxo Inc., GlaxoWellcome and finally GlaxoSmithKline. Leaving his position as a Director at GlaxoSmithKline Research and Development laboratories at Research Triangle Park, N.C. USA, Dr. Kenakin is now a professor in the Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill. Currently he is engaged in studies aimed at the optimal design of drug activity assays systems, the discovery and testing of allosteric molecules for therapeutic application and the quantitative modeling of drug effects. In addition, he is Director of the Pharmacology curriculum at the UNC School of Medicine. He is a member of numerous editorial boards as well as editor in Chief of the Journal of Receptors and Signal Transduction and Co-editor in Chief of Current Opinion in Pharmacology. He has authored numerous articles and has written 10 books on Pharmacology.

Bryan L. Roth, MD, PhD

University of North Carolina School of Medicine

Bryan Roth MD, PhD, is the Michael Hooker Distinguished Professor of Pharmacology at UNC Chapel Hill Medical School. Dr. Roth received postdoctoral training in molecular pharmacology at NIH and his psychiatry training at Stanford. His research interests include chemical and synthetic biology particularly as they apply to G-protein coupled receptors. He has published nearly 400 papers and given 100's of invited talks. Dr. Roth serves on the boards of many pharmacology and chemistry journals and, in addition, is currently the Deputy Editor of the Journal of Clinical Investigation. Dr. Roth also directs the National Institute of Mental Health's small molecule screening program--now in its 16th year. Over the past 5 years, this program (NIMH-PDSP) has facilitated work on more than 500 projects and contributed to more than 500 publications and patents assisting investigators world-wide.

JoAnn Trejo, PhD

University of California, San Diego

Dr. JoAnn Trejo (BS, UC Davis and PhD, UC San Diego) is a Professor in the School of Medicine at the University of California, San Diego. Dr. Trejo conducts research, published in > 60 papers, focused on defining the pathways that regulate vascular inflammation and breast cancer progression. She has received numerous grants from the National Institutes of Health (NIH), Komen Foundation, UC Tobacco-related Disease Research Program and the American Heart Association (AHA) including the prestigious AHA Established Investigator Award. Dr. Trejo is a leader in the scientific community. She was elected to serve on Council of the American Society for Cell Biology (ASCB), as Chair of Gordon Research Conferences and a member of several NIH Study Sections. Dr. Trejo is committed to increasing the diversity of science and gives frequent lectures on this topic. She is a Life member of Society for the Advancement of Chicanos and Native Americans in Science (SACNAS), a member of the ASCB Women in Cell Biology Committee, ASCB Minority Affairs Committee and Keystone Symposia Diversity Advisory Committee. Dr. Trejo is the recipient of the 2015 American Society for Biochemistry and Molecular Biology Ruth Kirchstein Diversity in Science Award. She is currently the Director of the San Diego Institutional Research and Academic Career Development Award (IRACDA), an NIH sponsored postdoctoral training program that aims to develop a diverse group of highly trained biomedical scientists and is the Vice Chair of Education in the Department of Pharmacology at UC San Diego.

Jonathan D. Violin, PhD

Trevena Inc.

Dr. Violin helped to launch Trevena in 2008 from its scientific foundations at Duke University, and leads Trevena’s investor relations program. Prior to this, he led Trevena’s biology group, focused on cardiovascular and CNS diseases, and was responsible for high throughput screening, cellular and molecular pharmacology, and in vivo pharmacology teams. He helped Trevena identify and progress three novel molecules to clinical development, including TRV027, now in a Phase 2b study for acute heart failure, and TRV130, now in Phase 2 studies for treating post-operative pain. Prior to joining Trevena, he was a post-doctoral fellow in the laboratory of Dr. Robert Lefkowitz at Duke University Medical Center, where he studied biased ligands and beta-arrestin functions for a variety of GPCRs. His research helped establish how biased ligands elicit unique cellular pharmacology with potential to translate into differentiated therapeutics. Dr. Violin holds a Ph.D. from the Department of Pharmacology at the University of California, San Diego, where he developed biosensors to study the spatial and temporal dynamics of kinase signaling. He also received an M.B.A. with a concentration in Health Sector Management from the Fuqua School of Business and a B.S. in Chemical Pharmacology from Duke University.

Sponsors

For sponsorship opportunities please contact Perri Wisotsky at pwisotsky@nyas.org or 212.298.8642.

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Grant Support

This activity is supported by an education grant from Lilly. For further information concerning Lilly grant funding visit www.lillygrantoffice.com.

This program is supported in part by a grant from Merck and Co., Inc.

This program is supported in part by a grant from Otsuka America Pharmaceutical, Inc.

Promotional Partners

The American Society for Pharmacology and Experimental Therapeutics (ASPET)

Chemistry Conferences

The Dana Foundation

Nature

Society for Neuroscience

Society of Biological Psychiatry


The Biochemical Pharmacology Discussion Group is proudly supported by


  • Merck
  • WilmerHale

Mission Partner support for the Frontiers of Science program provided by Pfizer

Abstracts

The Paradigm of GPCR Functional Selectivity and Implications for Drug Development
John A. Allen, PhD, Pfizer, Inc.

G protein-coupled receptors (GPCRs), the single largest class of druggable targets in therapeutic drug discovery, signal via canonical pathways involving heterotrimeric G proteins, and also via G protein–independent interactions with other signaling proteins, including the β-arrestins. The ability of natural or synthetic ligands to cause receptors to engage one signaling protein and pathway over another results in functional selectivity or ligand biased signaling. This brief presentation will introduce the concept of GPCR functional selectivity providing historical and recent examples of biased ligand activity and overview approaches to identify, quantify and validate GPCR biased ligands. Discussion will address how the emergence of GPCR functional selectivity has created a paradigm shift that is redefining drug action and providing new opportunities for drug development.
 

Beyond Signaling Bias
Terry Kenakin, PhD, University of North Carolina at Chapel Hill School of Medicine

The parsimonious idea that all agonists stabilize a single receptor active state has now given way to ideas describing multiple agonist-stabilized receptor states that can bias their stimulus toward different cellular signaling pathways. A brief description of the evolution of the Biased Receptor Signaling Model will be given as a preface to discussion of the three most prominent methods for quantification of this effect and also translation to in vivo therapy. This latter topic will include discussion of cell-based bias and the inherent problems in predicting therapeutic agonist response this produces and also the examination of differences between 'Efficacy-dominant' and 'Affinity-dominant' bias with attention to how these two modes of action will produce differences in vivo.
 

How Much Bias do we Need? Elucidating Ligand-Directed Signaling in vivo
Laura Bohn, PhD, The Scripps Research Institute

The kappa opioid receptor (KOR) is a potential therapeutic target for the treatment of diverse conditions ranging from depression, stress, addiction, pain and intractable itch. Activation of this receptor has been shown to induce aversive and dysphoric states yet activation of the KOR can also produce antinociception and alleviate itch. Therefore, there may be an opportunity to refine KOR-directed agonists to optimize therapeutic approaches while preventing certain side effects. There is emerging evidence that the dysphoric and aversive effects of KOR activation may be mediated via a barrestin2-dependent mechanism. In a collaborative drug discovery effort, we have identified KOR agonists that display biased towards G protein signaling and away from barrestin2-recruitment. In mice, the G/barrestin2 biased agonists produce antinociception and suppress itch; however, other behaviors are notably unaffected. Therefore it may be possible to refine agonist-directed signaling at KOR in order to improve therapeutic potential. This work is supported by an NIH MPI R01 DA031927 to LMB and J. Aubé.
 

Glycosylation of Protease-activated Receptor-1 Regulates G Protein Signaling Pathway Bias
JoAnn Trejo, PhD, University of California, San Diego

Protease-activated receptor-1 (PAR1) is a G protein-coupled receptor (GPCR) for thrombin and plays a pivotal role in hemostasis, thrombosis and inflammatory responses to tissue injury. Thrombin cleaves the N-terminus of PAR1, generating a new N-terminal domain that functions as a tethered ligand by binding intramolecularly to residues on the surface of extracellular loop 2 (ECL2) to elicit transmembrane signaling through multiple G protein subtypes including Gq, G12/13 and Gi. However, the mechanisms that control activated PAR1 wildtype coupling to distinct G protein subtypes are not known. We recently discovered that N-linked glycosylation of PAR1 wildtype at ECL2 dictates differential coupling to Gq versus G12/13 signaling. Thrombin activation of PAR1 wildtype caused robust G12/13-dependent RhoA activation and stress fiber formation, whereas a glycosylation-deficient PAR1 NA ECL2 mutant displayed minimal RhoA signaling and virtually no change in stress fiber formation. Activated PAR1 wildtype also exhibited greater associated with G12/13 proteins compared to mutant receptor. In contrast, activation of PAR1 NA ECL2 mutant by thrombin resulted in enhanced Gq-stimulated PLC-b-mediated phosphoinositide hydrolysis and cellular proliferation compared to wildtype receptor. The PAR1 NA ECL2 mutant also showed a greater capacity to associate with Gq unlike the wild-type receptor. Inhibition of endogenous PAR1 N-linked glycosylation using pharmacological agents also switched coupling from predominantly G12/13 to Gq signaling in cultured human endothelial cells. Together these findings suggest that N-linked glycosylation of PAR1 at ECL2 is critical for stabilizing different active receptor conformations that facilitate coupling to distinct heterotrimeric G protein subtypes and regulates signaling pathway bias.
 

Extending the Bitopic Ligand Paradigm: A Novel Mechanism of Allostery in a G Protein-coupled Receptor Dimer
Jonathan A Javitch, MD, PhD2,3

SB269652 is to our knowledge the first drug-like allosteric modulator of the dopamine D2 receptor (D2R), but it contains structural features associated with orthosteric D2R antagonists. Using a functional complementation system to control the identity of individual protomers within a dimeric D2R complex, we converted the pharmacology of the interaction between SB269652 and dopamine from allosteric to competitive by impairing ligand binding to one of the protomers, indicating that the allostery requires D2R dimers. Additional experiments identified a 'bitopic' pose for SB269652 extending from the orthosteric site into a secondary pocket at the extracellular end of the transmembrane (TM) domain, involving TM2 and TM7. Engagement of this secondary pocket was a requirement for the allosteric pharmacology of SB269652. This suggests a new mechanism whereby a bitopic ligand binds in an extended pose on one G protein-coupled receptor protomer to allosterically modulate the binding of a ligand to the orthosteric site of a second protomer.
 
Coauthor: J Robert Lane, PhD1, Prashant Donthamsetti, MSc2,3, Jeremy Shonberg, PhD4, Chris J Draper-Joyce, BSc1,Samuel Dentry, BSc1, Mayako Michino, PhD5, Lei Shi, PhD5,6, Laura López, PhD1, Peter J Scammels, PhD4,Benvenuto Capuano, PhD4, Patrick M Sexton, PhD1, Arthur Christopoulos, PhD1
 
1Drug Discovery Biology, Department of Pharmacology, Monash Institute of Pharmaceutical Sciences, Monash University
2Departments of Psychiatry, and Pharmacology, College of Physicians and Surgeons, Columbia University
3Division of Molecular Therapeutics, New York State Psychiatric Institute
4Department of Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University
5Department of Physiology and Biophysics, Weill Medical College of Cornell University
6Institute for Computational Biomedicine, Weill Medical College of Cornell University

 

Keynote Presentation: A Brief History of β-arrestins: From Birth to Bias
Robert J. Lefkowitz, MD, Duke University Medical Center

Structural features responsible for GPCR functional selectivity
Bryan Roth, MD, PhD, University of North Carolina at Chapel Hill School of Medicine

This talk will highlight new and emerging findings from high resolution GPCR structures which yield insight into the mechanism(s) responsible for biased signaling (G protein vs arrestin). Additionally new data regarding the structural features responsible for biased signaling mediated by positive allosteric modulators will also be presented. Finally, it will be shown how high resolution GPCR structures informs drug design with new case studies.
 

Implications for GPCR Functional Selectivity/Biased Signaling in the Actions of Dopamine
Marc G. Caron, PhD, Duke University Medical Center

Many CNS disorder symptoms are treated with therapeutic agents that target G protein-coupled receptors (GPCR) and D2 dopamine receptors (D2R), the main target of clinically effective antipsychotics, represent a good example. We now understand that GPCRs can signal through both G proteins and the ability of beta-arrestins to scaffold signaling complexes with distinct temporal and pharmacological properties and biased ligands can selectively discriminate between these modes of signaling. We have previously shown that D2R can engage an Akt/GSK3 signaling pathway through a beta-arrestin2 dependent signaling complex. To further validate the physiological role of this signaling pathway, we have used genetic approaches like the neuron selective deletion beta-arrestin2, the downstream GSK3beta gene to confirm their mimic of antipsychotic actions. Novel aripiprazole-based D2R/beta-arrestin2 functionally selective ligands have also been developed (Allen et al, 2011) that show antipsychotic-like activity in amphetamine and PCP animal models of psychotic-like behaviors. In mice lacking beta-arrestin2 in select neurons, inactivation of beta-arrestin2 in D2R-expressing neurons reduces behavioral responses to amphetamine but not to PCP. Furthermore, one the beta-arrestin biased D2R ligands, UNC9994, failed to inhibit the amphetamine response in mice lacking beta-arrestin2 in all D2R neurons, but showed neuronal selectivity for PCP induced responses. In addition, we have developed mutant D2Rs that can selectively signal either through the G protein- or beta-arrestin-dependent pathways in the hope of being able to reconstitute these functionally selective receptors in vivo. These approaches should facilitate identification of unique and previously unappreciated cellular and molecular of targets of D2R signaling and antipsychotic actions.
 

First Clinical Evidence That Biased Ligands Improve GPCR Therapeutic Pharmacology
Jonathan Violin, PhD, Trevena, Inc

Drug discovery targeting GPCRs classically sought agonists or antagonists to activate or inhibit cellular responses associated with a particular receptor. GPCRs are now recognized to support a broader range of pharmacological profiles, a concept broadly referred to as functional selectivity. In particular, “biased ligands” may be able to optimize the balance of beneficial and adverse on-target effects by stabilizing subsets of receptor conformations compared to classical agonists or antagonists. This has suggested an opportunity to deliver safer, better tolerated, and more efficacious drugs than current GPCR-targeted medicines, many of which suffer severe limitations. Trevena has discovered several biased ligands now in clinical development, including TRV027 for acute heart failure and TRV130 for moderate-to-severe pain. These ligands target the angiotensin II type 1 receptor and the mu opioid receptor, respectively, and illustrate the translation of the biased ligand concept from basic biology to clinical drug development. Early clinical data for both compounds supports their differentiation and potential clinical utility.
 

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