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Allosteric Modulation of G Protein-Coupled Receptors: Opportunities and Challenges for Drug Discovery


for Members

Allosteric Modulation of G Protein-Coupled Receptors: Opportunities and Challenges for Drug Discovery

Tuesday, February 28, 2012

The New York Academy of Sciences

Allosteric modulation of G protein-coupled receptors is rapidly emerging as a potentially powerful therapeutic strategy. Allosteric modulators, which interact with binding sites topologically distinct from the orthosteric ligand binding sites, can potentially provide improved selectivity and safety, along with maintenance of spatial and temporal regulation of receptor signaling. The identification and assessment of allosteric lead molecules, as well as the progression of allosteric modulators to clinical candidates, comes with a unique set of challenges. This symposium discusses current and emerging strategies, as well as potential pitfalls, specifically related to the prosecution of allosteric modulator programs. Particular focus will be given to screening strategies for allosteric modulators and in vitro assessment of allosteric modulator activity.

Registration Pricing

Student / Postdoc / Fellow Member:$0
Student / Postdoc / Fellow Nonmember:$15


Presented by

  • American Chemical Society, New York Section
  • The New York Academy of Sciences


* Presentation times are subject to change.

Tuesday, February 28, 2012

12:30 PM


1:00 PM

Andrew Alt, PhD, Bristol-Myers Squibb

1:10 PM

Positive Allosteric Modulators of Metabotropic Glutamate Receptor 5 for Treatment of Schizophrenia
P. Jeffrey Conn, PhD, Vanderbilt University

1:50 PM

Novel Paradigms in the World of Allosteric Ligands of GPCRs
Celine Valant, PhD, Monash University

2:30 PM

A Multi-Platform, Technology-Enabled Approach to Lead Optimization in the GPCR Modulator Space
Adam Hendricson, PhD, Bristol-Myers Squibb

3:10 PM

Coffee Break

3:40 PM

The Opportunity and Challenge of Allosterism in GPCR Drug Discovery
Christian Felder, PhD, Eli Lilly and Company

4:20 PM

Panel Discussion
All speakers, moderated by Andrew Alt, PhD, Bristol-Myers Squibb

5:00 PM

Networking Reception



Andrew Alt, PhD

Bristol-Myers Squibb

Andrew Alt, Ph.D. heads the GPCR & Ion Channel Lead Discovery team at Bristol-Myers Squibb Company. He has extensive research experience in allosteric modulators of GPCR and ligand-gated ion channel targets. Dr. Alt received his Ph.D. from the University of Michigan and did post-doctoral research at the Indiana University Medical School. He has worked in drug discovery settings ranging from “big pharma” to biotech, having contributed to early-phase discovery research at Eli Lilly and Co., Pfizer, and EPIX Pharmaceuticals prior to joining Bristol-Myers Squibb in 2008.

Jennifer Henry, PhD

The New York Academy of Sciences


P. Jeffrey Conn, PhD

Vanderbilt University

Dr. Conn is the Lee E. Limbird Professor of Pharmacology at Vanderbilt University and Director of the Vanderbilt Center for Neuroscience Drug Discovery. Dr. Conn received the Ph.D. degree in Pharmacology from Vanderbilt in 1986 and pursued postdoctoral studies at Yale University. Dr. Conn joined the faculty of the Department of Pharmacology at Emory University in 1988 where he where he established himself as a leader in studies of neurotransmitter receptors and their roles in regulating brain function in circuits involved in psychiatric and neurological disorders. In 2000, Dr. Conn assumed the position of Senior Director and Head of the Department of Neuroscience at Merck and Company in West Point, PA. Dr. Conn moved to Vanderbilt University in 2003 as the founding director of the Vanderbilt Program in Drug Discovery (VPDD), with a primary mission of facilitating translation of recent advances in basic science to novel therapeutics. By 2011 the VPDD had grown to approximately 100 full time scientists and raised over $80M in research funding. In addition, the VPDD advanced novel molecules from three major programs into development for clinical testing in major brain disorders with industry partners. A fourth program reached development status and is advancing internally at Vanderbilt. To mark this growth and facilitate more fluid integration of drug discovery, development, and corporate partnerships, the VPDD achieved independent center status and was named the Vanderbilt Center for Neuroscience Drug Discovery in January 2011. Dr. Conn is Editor in Chief of Molecular Pharmacology, Regional Editor (North America) of Current Neuropharmacology and serves on the editorial boards of 6 other international journals. He has served the Scientific Advisory Boards of multiple foundations and companies in the pharmaceutical and biotech industries, He currently serves as the founding director of the scientific advisory board of Karuna Pharmaceuticals and on the advisory boards of Seaside Therapeutics and the Michael J. Fox Foundation. He served as Chairman of the Neuropharmacology Division of the American Society for Pharmacology and Experimental Therapeutics (ASPET) and on multiple national and international committees. He has received numerous awards, including the NARSAD Essel Distinguished Investigator Award, the ASPET-Astellas Award in Translational Pharmacology, the Pharmacia - ASPET Award for Experimental Therapeutics, the Charles R. Park Award for Basic Research Revealing Insights into Physiology and Pathophysiology, the PhRMA Foundation Award for Excellence in Pharmacology and Toxicology. He was named as an ISI Most-Cited Scientists in Pharmacology & Toxicology and the Lee University 2008 Distinguished Alumnus of the Year. Dr. Conn’s current research is focused on development of novel treatment strategies for schizophrenia, Parkinson’s disease, and other serious brain disorders.

Christian Felder, PhD

Eli Lilly and Company

Dr. Christian Felder received his PhD in 1987 in the Dept. of Biochemistry at Georgetown University School of Medicine. He joined the NIMH in Bethesda, MD as a staff fellow in 1987 and completed his postdoctoral training in the laboratory of Dr. Julius Axelrod in 1990. He remained at the NIMH as Head of the Unit on Cell and Molecular Signaling where his lab focused on the molecular mechanisms of neurotransmitter action and their role in neuropsychiatric diseases. In 1997, he joined the Neuroscience Division at Eli Lilly & Co. in Indianapolis, IN and has held both research and management positions in the US and UK. He is currently a Research Fellow in Neuroscience leading research and drug development projects.

Adam Hendricson, PhD

Bristol-Myers Squibb

Adam Hendricson received his doctorate in Pharmacology from Tulane University studying the role of GPCRs in hearing and balance, followed by post-doctoral training in addiction neurobiology at the Waggoner Center for Addiction Research, Univ. Texas at Austin and 3 years in biotech at Neuromed (now Zalicus) before joining Bristol-Myers Squibb in 2007. In his current position in Lead Evaluation at BMS, Adam’s research focus includes cellular assay design and technology development for lead optimization in the CNS space.

Celine Valant, PhD

Monash University, Victoria, Australia

Dr. Celine Valant is a Research Fellow in the Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Monash University, Victoria, Australia. Dr Valant obtained a Bachelor of Chemistry and Biology (2001) and a Bachelor of Medicinal Chemistry (Honours; 2002) at the Universite Louis Pasteur in Strasbourg, FRANCE. She completed a PhD in 2005 at The University of Pharmacy, Strasbourg under the supervision of Professor Marcel Hibert where she focused on the synthesis of receptor conformation state-specific allosteric inhibitors of the tachykinin NK2 receptor and of muscarinic receptor modulators. She then took up a postdoctoral position in molecular pharmacology with Professors Arthur Christopoulos and Patrick M. Sexton, at Monash University, Melbourne. Dr Valant’s expertise is in the study of G protein coupled receptors (GPCRs), and she has established an international profile in the synthesis and study of allosteric ligands at GPCRs. Moreover, she was instrumental in the discovery of a new class of hybrid orthosteric-allosteric GPCR ligands, termed “bitopic”. The principal interest of her research is towards understanding the modes of regulation of GPCRs in an effort to identify novel targets or approaches for drug discovery. Her research interests encompass allosterism, differential signaling, interaction of receptors with regulatory accessory proteins and drug design. She is an author of 16 scientific articles, 2 reviews and 2 book chapters. She is reviewer of 5 international journals.


Presented by

  • American Chemical Society, New York Section

Grant Support

This activity is supported by an educational grant from Lilly USA, LLC. For further information concerning Lilly grant funding, visit

Academy Friends

ASPET's Division for Drug Discovery, Development, & Regulatory Affairs

Bristol-Myers Squibb

Promotional Partner

The Dana Foundation


Postive Allosteric Modulators of Metabotropic Glutamate Receptor 5 for Treatment of Schizophrenia
P. Jeffrey Conn, PhD, Vanderbilt University

A large number of cellular and behavioral studies suggest that selective activators of the metabotropic glutamate receptor (mGluR) mGluR5 could provide a novel approach to treatment of schizophrenia. Especially exciting is the possibility that such agents could have efficacy in treatment of positive, negative, and cognitive symptoms in schizophrenia patients. We have been highly successful in developing multiple series of highly selective positive allosteric modulators of mGluR5 that have robust effects in animal models that have been used to predict efficacy of novel antipsychotic agents. Multiple structurally distinct mGluR5 PAMs have been identified and in vivo efficacy in animal models used to predict efficacy in treatment of positive symptoms has been verified with at least 9 distinct chemical series. In addition, mGluR5 PAMs enhance multiple forms of synaptic plasticity in the CNS and have cognition-enhancing effects in rodent models.
These studies provide an exciting new approach to discovery of novel highly selective activators of mGluR5 for treatment of schizophrenia. In addition, recent advances in discovery of a broad range of mGluR5 modulators with different functional profiles is allowing development of a more complete understanding of the properties of individual mGluR5 PAMs that may be most suitable for development of novel therapeutic agents. These differences in the in vitro profiles of different mGluR5 PAMs raises potential opportunities for developing subtly different therapeutic agents However, this also raises challenges in knowing the optimal balance of properties for clinical candidates. We have identified "molecular switches" in some chemical scaffolds that allow subtle chemical changes to convert an mGluR5 PAM to an mGluR5 NAM. We avoid such scaffolds as this property presents a challenge for chemical optimization and may yield active metabolites that counteract the in vivo effects of a parent compound. In addition, we have shown that in vivo occupancy at an identified allosteric site bears a close relationship with efficacy for some scaffolds whereas this relationship is lost for other compounds that do not bind in a competitive manner with this site. Finally, some scaffolds display allosteric agonist activity in vitro whereas others are pure mGluR5 PAMs. Optimization of ago-PAMs and related pure mGluR5 PAMs revealed that allosteric agonist activity is not critical for efficacy in animal models that were studied. However, robust allosteric agonist activity can lead to adverse effects in animal models. These studies provide valuable insights that are guiding lead optimization efforts aimed at advancing novel mGluR5 PAMs into clinical development.

Novel Paradigms in the World of Allosteric Ligands of GPCRs
Celine Valant, PhD, Monash University

It is now well established that virtually all GPCRs possess topographically distinct allosteric binding sites that can be targeted to modulate the activity of orthosteric ligands. Accordingly, recent years have seen a dramatic increase in the discovery of allosteric GPCR modulators. A key challenge to the field is the means to optimally describe allosteric effects in a manner that can capture experimentally observed observations and facilitate enriched structure-activity studies and/or inform drug candidate selection matrices. One approach to this challenge is to assign numbers to allostery using operational modeling. Such models describe GPCR allosterism minimalistically in terms of modulator affinity (KB) for the free receptor, modulation of the binding (α) and/or signaling (β) of the orthosteric ligand, and intrinsic agonism (τB) of the allosteric modulator itself; it is apparent that most allosteric ligands are likely to display mixtures of these properties in a cell-dependent manner. Another recent paradigm that has emerged from the study of GPCR allostery is the concept of the 'bitopic' ligand, i.e., compounds composed of distinct orthosteric and allosteric pharmacophores joined by an appropriately chosen linker. An advantage of such ligands is the ability to ensure receptor activation/inactivation through an appropriately chosen orthosteric moiety, while inducing either subtype and/or functional selectivity through the allosteric moiety. With the recent resolution of multiple Family A GPCR crystal structures, the possibility of more rational exploitation of novel binding pockets either above or below the orthosteric site promises to facilitate true structure-based drug discovery for allosteric GPCR ligands.

A Multi-Platform, Technology-Enabled Approach to Lead Optimization in the GPCR Modulator Space
Adam Hendricson, PhD, Bristol-Myers Squibb

Allosteric Modulation of GPCRs presents both biological and technological challenges. In Lead Evaluation at BMS, our approach to providing highly precise SAR vectors around multiple indices of compound activity in vitro is heavily technology-enabled. Our guiding principle is that detection of activity in vitro in multiple modes (eg, PAM, NAM, agonist, etc) is key to fully articulating SAR information in the GPCR modulator space due to "knife edge" SAR characteristics whereby fluid interplay among biological modes of activity can attend subtle chemical changes. In service of this principle, we have leveraged technology to build multi-mode assay and informatics platforms for both Hit ID and Lead Optimization which are both highly precise and scaleable with portfolio needs. We have platforms in place to provide highly granular, high throughput SAR determinations on both potency and efficacy in the often-challenging modulator biology space. Here, we will discuss the reduction to practice of this technical, biological, and informatic architecture in the context of "real world" drug hunting scenarios unique to GPCR modulators.

The Opportunity and Challenge of Allosterism in GPCR Drug Discovery
Christian Felder, PhD, Eli Lilly and Company

Neurotransmitters bind GPCRs at their native orthosteric sites initiating signal transduction events that can modify synaptic function or control metabotropic cellular remodeling. Small molecule drug discovery has historically targeted the GPCR orthosteric binding site which has been largely successful for creating neutral antagonists and inverse agonists. However, developing orthosteric agonist ligands has been more challenging due to receptor subtype selectivity issues when high sequence homology exists, unknown biased signaling requirements, receptor-activated desensitization and down-regulation, and a lack of understanding of the functional consequences of full vs partial agonists. To address some of these challenges, allosteric binding sites that are topographically distinct from the orthosteric domain have been targeted in recent years. Positive and negative allosteric modulators are hypothesized to modify normal, phasic neurotransmitter function, preserving spatial and temporal signaling and therefore, physiological relevance. Evidence suggests that allosteric binding sites are less conserved compared to orthosteric sites, allowing for the development of highly selective ligands that have the potential to normalize neural systems damaged in severe neuropsychiatric and neurological diseases such as schizophrenia, depression, anxiety, pain, Alzheimer’s and Parkinson’s diseases. Examples will be provided illustrating the challenges in developing positive allosteric modulators (PAMs) for the muscarinic acetylcholine M4 receptors, as well as the metabotropic glutamate receptor-2 (mGluR2) subtype. Highly selective and cooperative PAMs for the M4 receptor (LY2033298) and the mGluR2 receptor (THIIC) have proven to be useful pharmacological tools to guide in vitro assay development, high throughput screening approaches, hit and lead optimization, and in vivo testing paradigms potentially predictive of efficacy in subsequent clinical studies. These tools can provide valuable lessons for future GPCR allosteric projects.

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