that bind or prevent binding to G protein-coupled receptors (GPCRs) have been successfully
developed into therapeutic agents. However, often details on how the drug
achieves its effect are not clear. Not only do GPCRs control multiple signaling
pathways, but GPCRs have their own complicated kinetic, cellular location and
signaling life cycle, which varies from one receptor type to another and its
cellular environment. Part 2 of our back-to-back GPCR meetings focuses on
recently tractable pharmacologic complexities in the field, receptor-associated
proteins that are emerging as drug targets and case-studies of lead compounds progressing
in development, especially allosteric modulators.
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Wednesday, September 23
11:30 am Registration
12:55 pm Plenary Keynote Program
2:40 Refreshment Break in the Exhibit Hall with Poster Viewing
3:25 Chairperson’s Opening Remarks
Paul Insel, Ph.D., Professor, Pharmacology & Medicine, University of California, San Diego
3:35 Exploring Protease-Activated Receptor Biased Signaling Inside and Outside of the Cell
JoAnn Trejo, Ph.D., Professor, Pharmacology, University of California, San Diego
PARs are a family of GPCRs that are uniquely activated by proteolysis. We have discovered that PAR1 exhibits biased signaling regulated through post-translational modifications and compartmentalization in caveolae. We are currently examining the molecular mechanisms by which PAR1 N-linked glycosylation controls G protein coupling specificity and how caveolae distribution affects endothelial PAR1 signaling induced by thrombin versus activated protein C.
4:05 Crystal Structures of Peptide-Bound RAMP-GPCR Complexes
Augen A. Pioszak, Ph.D., Assistant Professor, Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center
Receptor activity-modifying proteins (RAMP1-3) are membrane proteins that associate with several GPCRs to modulate their pharmacology. RAMPs of class B GPCR calcitonin receptor-like receptor (CLR) are thought to determine the peptide ligand binding preferences of the receptor. I present two high-resolution crystal structures of peptide-bound CLR:RAMP extracellular domain complexes that reveal how peptides selectively bind and may inform drug development targeting these complexes.
4:35 Sponsored Presentation (Opportunity Available)
5:05 Refreshment Break in the Exhibit Hall with Poster Viewing
5:40 Structure and Function of the Hypertension Variant A486V of G Protein-Coupled Receptor Kinase 4
Kevin Lumb, Ph.D., Director, Discovery Technologies, Janssen R&D LLC
G protein-coupled receptor (GPCR) kinases (GRK) bind to and phosphorylate GPCRs, initiating the process of GPCR desensitization and internalization. GRK4 is implicated in the regulation of blood pressure, and GRK4 polymorphisms are associated with hypertension. Here we present work performed at Merck on the X-ray structure and autophosphorylation of the human GRK4 hypertension variant A486V
6:10 Heterologous Desensitization of GPCR-RTK Transactivation
Michael Beazely, Ph.D., Assistant Professor, School of Pharmacy, University of Waterloo, Canada
A typical GPCR-initiated receptor tyrosine kinase (RTK) transactivation pathway results in a transient activation and phosphorylation of the RTK and downstream effector. We have recently demonstrated that after this transient transactivation, there is ~ 3 hour blackout period where the RTK can not be “re-transactivated”, either by repeated exposure to the same GPCR agonist, or to different GPCR agonists.
6:40 Close of Day
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Thursday, September 24
7:30 am Registration
8:00 Interactive Breakfast Breakout Discussion Groups
8:45 Chairperson’s Remarks
Andrew Alt, Ph.D., Director, Cell-Based Screening Technologies, Bristol-Myers Squibb
8:50 KEYNOTE: The Activated Conformation of GPCRs and the Mechanism of Activation of G Proteins
Roger K. Sunahara, Ph.D., Professor of Pharmacology, Department of Pharmacology, University of Michigan Medical School
I will describe the application of conformation-specific single-domain antibodies (nanobodies) to directly probe activation of the β2-adrenoceptor and its cognate G protein. Our results show that the adrenergic agonist not only promotes receptor and G protein activation in the plasma membrane as expected, but also in the early endosome membrane, and that internalized receptors contribute to the overall cellular cyclic AMP response within several minutes after agonist application.
9:25 GPCR Trafficking and Endosomal Signaling
Adriano Marchese, Ph.D., Associate Professor, Pharmacology, Stritch School of Medicine, Loyola University Chicago
Membrane trafficking plays an important role in governing the magnitude and duration of GPCR signaling. It is now emerging that targeting novel aspects of GPCR trafficking could impact GPCR signaling and cellular responsiveness. This talk will focus on recent advances and highlight how targeting novel aspects of GPCR trafficking could be a useful strategy to treat diseases involving GPCRs.
9:55 Opioid Receptor Trafficking, Signaling and Physiology
Manoj Puthenveedu, Ph.D., Assistant Professor, Biological Sciences and The Center for the Neural Basis of Cognition, Carnegie Mellon University
The use of opioids in pain management has been limited by adverse effects Efforts to identify better opioids with fewer limitations have had little success. I will discuss our work on the mechanisms of opioid receptor trafficking, which could potentially be used as a convergent strategy to regulate opioid responses by actively manipulating the localization of opioid receptors.
10:25 Coffee Break in the Exhibit Hall with Poster Viewing and Poster Winner Announced
11:10 Receptor Binding Kinetics in GPCR Drug Discovery: The Good, the Bad, and the Confusing
Brian J. Murphy, Ph.D., Senior Principal Scientist, Fibrosis Drug Discovery, Bristol-Myers Squibb
Drug residence time is being increasingly appreciated as an important factor in GPCR compound optimization. Lack of efficacy of high affinity compounds can sometimes be explained by less than optimal receptor off-rates. Several low throughput methods used to determine kinetic parameters exist, but one can obtain different kinetic parameter values depending on which methodology is employed. Which is the correct off-rate to use for optimization?
11:40 Targeting Glutamate Receptors for Stress-Related Disorders
Sylvain Celanire, Ph.D., Co-Founder and CEO, Pragma Therapeutics
12:10 pm Sponsored Presentation (Opportunity Available)
12:40 Session Break
12:50 Luncheon Presentation (Sponsorship Opportunity Available) or Lunch on Your Own
1:30 Refreshment Break in the Exhibit Hall with Poster Viewing
2:15 Chairperson’s Remarks
Dario Doller, Ph.D., Director, Discovery Chemistry and Chemical Biology, Lundbeck Research
2:20 Identification of Orthosteric and Allosteric Residues Important for FFAR1 Binding and Function
Gayathri Swaminath, Ph.D., Principal Scientist, Metabolic Disorders, Amgen
Fatty acids are considered orthosteric ligands for free fatty acid receptor (FFA1 receptor). Several FFA1 receptor mutants were generated to identify the potential sites that may allosterically regulate the orthosteric ligand’s function. Mutational analysis revealed previously unidentified sites that may allosterically regulate orthosteric ligand function including residues that are important for the interactions between orthosteric and allosteric binding sites.
2:50 Allosteric Ligands of Metabotropic Glutamate Receptor 5 Have Biased Agonism and Cooperativity
Karen Gregory, Ph.D., Postdoctoral Fellow, Laboratory of Arthur Christopolous, Department of Drug Discovery Biology, Monash University, Australia
Drugs targeting metabotropic glutamate receptor 5 (mGlu5: a class C GPCR) have promising preclinical profiles but potential adverse effects. On-target adverse effects of certain allosteric modulators may be due to specific ligand scaffolds which result in modulation of distinct mGlu5 signaling pathways and receptor regulation processes. Establishing a “biased modulation fingerprint” can provide a framework for future novel biased allosteric modulator discovery for mGlu5.
3:20 Session Break
3:30 Identifying Bias in CCR1 Antagonists
Annette Gilchrist, Ph.D., Assistant Professor, Pharmaceutical Sciences, Midwestern University
Six compounds targeting CCR1 have undergone clinical testing for several different diseases (multiple sclerosis, rheumatoid arthritis, and chronic obstructive pulmonary disease). There has been some speculation that CCR1 may also play a role in multiple myeloma and pain modulation. We compared several allosteric inhibitors for their ability to alter binding of 125I-CCL3, beta-arrestin translocation, surface expression of CCR1, and chemotaxis.
4:00 Discovery of a Biased Incretin Receptor Agonist
Peter DiStefano, Ph.D., CSO, Zebra Biologics
We combined autocrine expression of very large peptide libraries to receptors in a cellular context to identify unique agonists to the GLP-1 receptor. We discovered rare, potent agonist peptides with amino acid sequences distinct from those of mammalian or reptilian GLP-1 that signal via G-proteins but not b-arrestin. These peptides are superior to Ex4 in glucose and insulin homeostasis parameters
4:30 Development and Characterization of Dopamine D3 Receptor Selective Compounds
Robert Luedtke, Ph.D., Professor, Pharmacology and Neuroscience, University North Texas Health Science Center
We have explored the use of dopamine D2-like (D2 and D3) receptor subtype selective ligands as therapeutic agents for the treatment of neurological disorders and as in-vivo PET imaging agents. We incorporate information provided by in vitro screens for D2-like
5:00 Close of Conference
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