Latecomers to the super-family of GPCRs, the metabotropic glutamate receptors (mGluRs) were not described until 1987 and were cloned in the early nineties. Today they are considered by many to be the single most promising new collection of targets for CNS drug discovery, with therapeutic potential to treat illnesses ranging from migraine to esophageal reflux, and from schizophrenia to Parkinson’s disease. Since the early nineties, advances and some unusual findings have come at a dizzying speed. The first talks will describe studies leading to the discovery that these GPCRs exist as obligate dimers with fascinating consequences for intramolecular signal transduction. Later discussion will introduce the role for mGLuRs in regulating glutamatergic neurotransmission and it’s effect on behavioral pharmacology and neurochemistry. With the advent of highly efficient cell-based screening techniques, it has been possible to identify an array of small molecules that have a variety of modulatory effects. The pharmacology of these novel compounds will be described, and we will see what they reveal about the role of mGlu4 and mGlu5 receptors in motor function related to Parkinson’s, and neuronal plasticity, respectively. The last two speakers will provide the therapeutic rationale for using CNS active small molecules for the treatment of schizophrenia, and the genetically linked fragile-X syndrome
This event is part of the Dr. Paul Janssen Memorial Series at the New York Academy of Sciences.
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*Presentation times are subject to change
1:00 – 1:10 PM
1:15 – 1:45 PM
Discovery, structure-function and molecular pharmacology of a family of GPCRs with unique architecture
1:50 – 2:20 PM
Antipsychotic efficacy of metabotropic glutamate receptors
2:25 – 2:55 PM
3:00 – 3:30 PM
HTS results from academia: Discovery of allosteric modulators for mGlu4 and mGlu5 receptors
3:35 – 4:05 PM
Discovery of a novel series of selective mGluR5 negative allosteric modulators
4:10 – 4:40 PM
Therapeutic implications of the mGluR theory of fragile X mental retardation
4:45 – 5:00 PM
Dr. Brodbeck received his undergraduate degree from the University of Wisconsin and his graduate degree from the department of Biochemistry, Biophysics and Genetics at the University of Colorado Health Sciences Center. He trained as molecular cell biologist, studying the intracellular transport of proteins. During his post-doctoral fellowship at the Washington university school of medicine, he studied GPCRs and the structure-activity relationship between ligand binding and functional activation. He continued his focus on GPCRs at Neurogen corporation, while studying the SAR of small molecule agonists and antagonists, and their effect on receptor function. More recently (2008), upon moving to Lundbeck Research USA, he continues his pursuit of small molecules which modulate the function of GPCRs, in an effort to discover novel drugs for CNS disorders.
Dr. Topiol received his undergraduate degree from City College of New York in Physics and his graduate degree from NYU in Physical Chemistry. He trained as a theoretical quantum chemist, developing ab initio electronic structure methods for large systems. He then post-docked at Northwestern with Mark Ratner and Arthur Frost, and at Carnegie-Mellon with John Pople (Noble laureate.) He started his full time employment as an academic at The Mount Sinai School of Medicine in the Department of Pharmacology. This marked his initial entry into biopharma in the area of CNS drugs acting on GPCRs. At that time, work on 5HT and histamine receptors was his main focus. Moving from there to industry, he started Computer Aided Drug Design groups Berlex, and later at Sandoz/Novartis. He has worked on all aspects of Computer Aided Drug Design, ranging from ligand based methods to structure based. Where possible, he worked on soluble protein targets that were amenable to iterative structure based design in an interdisciplinary project environment. His Drug Descovery research covered various therapeutic areas including cardiovascular disease, oncology and others. More recently (2004) upon moving to Lundbeck Research, USA and he has come full circle with an emphasis on GPCRs. Over the years, he has also worked on chiral recognition, receptor theory and combinatorial chemistry.
Mark F. Bear, Ph.D
Massachusetts Institute of Technology
Dr. Mark Bear is an Investigator of the Howard Hughes Medical Institute, and Picower Professor of Neuroscience in The Picower Institute for Learning and Memory and the Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology. Dr. Bear served as Director of The Picower Institute from 2007 to 2009. Prior to moving to MIT in 2003, Dr. Bear was on the faculty of Brown University School of Medicine for 17 years. After receiving his B.S. degree from Duke University, he earned his Ph.D. degree in neurobiology at Brown. He took postdoctoral training from Wolf Singer at the Max Planck Institute for Brain Research in Frankfurt, Germany, and from Leon Cooper at Brown. His honors include Young Investigator Awards from The Office of Naval Research (1988) and Society for Neuroscience (1993), and the Brown University Class of 2000 Barrett Hazeltine Citation for Teaching Excellence. He was elected as a Fellow of The Neurosciences Institute and Dana Alliance for Brain Initiatives in 1999, the American Association for the Advancement of Science in 2003, the American Academy of Arts and Sciences in 2004, and the American College of Neuropsychopharmacology in 2005. In 2006, Dr. Bear was the recipient of the William & Enid Rosen Research Award for outstanding contributions to our understanding of Fragile X by The National Fragile X Foundation.
Bita Moghaddam, Ph.D
University of Pittsburgh
Bita Moghaddam, PhD is Professor of Neuroscience and Psychiatry, at the University of Pittsburgh. She is the author of over 100 scientific papers and has extensive expertise in using animal models to study the cellular basis of cognitive constructs that are critical to psychiatric disorders including schizophrenia. She has a longstanding track record of involvement in successful translational research and is an effective educator and mentor. Her research has led to the discovery of the first non-monoamine targeting compound for treatment of schizophrenia. This novel therapeutic approach (targeting metabotropic glutamate receptors) was conceptualized by Dr. Moghaddam on the basis of her preclinical work. Her research has been funded continuously since 1991 including a MERIT award from that National Institute of Mental Health. She has been an active educator throughout her scientific career. Her education experience involves extensive didactic teaching of neuroscience to undergraduates, graduate students, medical students, and residence. She has been mentor to numerous pre and post-doctoral fellows. She is the recipient of many prestigious awards including the Efron award for excellence in research related to neuropsychopharmacology and the Paul Jansen Award for excellence in schizophrenia research. She serves on numerous editorial and advisory boards as well as national and local educational and service oriented committees.
Colleen Niswender, Ph.D
Vanderbilt University School of Medicine
Colleen Niswender obtained her Ph.D. in pharmacology in the lab of Dr. Ronald Emeson at Vanderbilt, studying the regulation of RNA editing in the mammalian central nervous system and characterization of molecular determinants regulating RNA editing events within the AMPA subtype glutamate receptor, GluR2, and the G protein-coupled 5HT 2C serotonin receptor. She then pursued postdoctoral studies with Dr. G. Stanley McKnight at the University of Washington, focusing on the study of Protein Kinase A signal transduction using recombinant mouse lines and genetically engineering mutations within the PKA enzyme. She joined the Vanderbilt Program in Drug Discovery in 2004 and has focused on the development of high throughput-compatible assays to search for ligands specific for G protein-coupled receptors (GPCRs) of the muscarinic and metabotropic glutamate receptor families. Currently, she directs the Molecular Pharmacology group within the Vanderbilt Program in Drug Discovery and is particularly interested in the concepts of functional selectivity and context-dependent pharmacology of allosteric modulators.
Jean-Philippe Pin, Ph.D
Université de Montpellier
Jean-Philippe Pin get his PhD in Molecular Biology in 1987 at the University of Montpellier 2 (France). He participated in the discovery of the metabotropic glutamate receptors and demonstrated synergism between various glutamate receptor subtypes for the activation of phospholipase A2. In 1990 he joined Steve Heinemann's laboratory at the Salk Institute as a post doctoral fellow. He cloned and characterized new mGlu receptor splice variants and demonstrated differences in their transduction properties. In 1992, he set up a research team working on the structure function relationship of mGlu receptors within a CNRS laboratory in Montpellier (France). Since 2003, he is head of the Molecular Pharmacology Department within the Institute of Functional Genomics (Montpellier, France). His research efforts are focused on the molecular and cellular dynamics of GPCRs, mostly mGlu and GABAB receptors, their regulation by intracellular proteins, and their modulation by new types of ligands. Thenks to the development of new technologies to study GPCRs, his studies led to new concepts in the GPCR field. These include that i) cell surface receptors can be activated by intracellular proteins; ii) GPCRs can be regulated by both negative and positive allosteric modulators; iii) dimerization is required for the activation of some GPCRs, and iv) GPCR dimers function in an asymmetrical way.
Jean-Philippe Rocher, Ph.D
Jean-Philippe Rocher is head of the Core Chemistry at Addex. He has been working with the company since inception and was responsible for establishing its chemistry department. He was director of chemistry at Devgen NV, Gent, Belgium from 2001 to 2002 and From 1997 to 2001, Dr. Rocher was senior research scientist for GlaxoSmithKline KK in Tsukuba, Japan. From 1995 to 1997 Dr Rocher was guest scientist at Mitsubishi Pharma in Yokohama, Japan. He obtained his PhD at the Faculty of Pharmacy of Lyon, France in 1987.
Discovery, structure-function and molecular pharmacology of a family of GPCRs with unique architecture.
Jean-Philippe Pin, Ph.D, Université de Montpellier
Metabotropic glutamate receptors were discovered in the mid 80's as G-protein coupled receptors activated by glutamate, and able to activate PLC. Further pharmacological, functional and cloning approaches revealed the existence of 8 different subtypes classified into three groups based on their sequence similarity, G-protein coupling specificity and pharmacological properties. Group-I mGluRs (mGluR1 and 5) are coupled to PLC and regulate post-synaptic events, while group-II (mGlu2 and 3), and group-III (mGlu4, 6, 7 and 8) are mostly pre-synaptic and regulate neurotransmitter release by activating Gi/o proteins. These receptors are complex proteins, composed of two identical subunits linked by a disulphide bridge, each composed of a large extracellular domain (ECD) where glutamate bind, and a 7TM domain responsible for G-protein activation. As based on the functional analysis of mutant receptors, and the structure resolution of the extracellular domain, it is now accepted that ligand binding in the ECD results in a relative movement of the subunits, then enabling activation of the 7TM domain. Of not whereas full activation is obtained when both binding sites are occupied, this lead to the activation of a single 7TM per dimer. In addition to glutamate analogs acting either as agonists or antagonists, screening campains in pharmaceutical industries revealed a number of allosteric modulators acting either as inverse non-competitive agonists, or as positive modulators enhancing both agonist efficacy and potency. Such ligands are often subtype selective, and most were found to pass the blood brain barrier, then offering new ways to modulate mGluR activity in animals. Thanks to the use of transgenic animals and the discovery of bioactive specific ligands, a wide number of possible therapeutic applications of mGluR ligands have been identified, from psychiatric disorders such as depression, anxiety or schizophrenia, to neurologic disorders including neurodegenerative diseases such as Parkinson's disease, through peripheral dysfunction including gastro-oesophagial reflux disease.
Antipsychotic efficacy of metabotropic glutamate receptors
Bita Moghaddam, Ph.D, University of Pittsburgh
Several lines of evidence suggest that NMDA receptor hypofunction may lead to some symptoms of schizophrenia, especially cognitive deficits such as impairments in working memory and attention that are dependent on the functional integrity of the prefrontal cortex (PFC). Furthermore, postmortem studies indicate that schizophrenia may be associated with reduced cortical GABA function. We have hypothesized that NMDA receptor hypofunction results in functional deficits of cortical GABA interneurons and that antipsychotic drugs ameliorate this deficit. In addition to traditional antipsychotic drugs, our work has shown that targeting metabotropic glutamate receptors (mGlu2/3 or mGlu5) also reduces the impact of NMDA hypofunction on cortical neuronal activity and on behavior. In recent studies we find that in behaving animals clozapine (and to a lesser degree, haloperidol) as well as a mGlu5 positive allosteric modulator reduce the impact of NMDA hypofunction on firing of cortical pyramidal and (putative) GABA neurons. The mGlu5 modulator also reduced the cognitive deficits associated with reduced NMDA receptor activity. These data indicate that activation of mGlu5 receptors similar to clozapine normalizes the disruptive effects of NMDA receptor hypofunction on activity of PFC pyramidal neurons and GABA interneurons. This mechanism may provide a physiological basis for the clinical efficacy of antipsychotic drugs.
HTS results from academia: Discovery of allosteric modulators for mGlu4 and mGlu5 receptors
Colleen Niswender, Ph.D, Vanderbilt University School of Medicine
Studies suggest that the metabotropic glutamate receptors are targets that should be explored in numerous neurological and psychiatric disorders such as Parkinson’s disease, schizophrenia, and Fragile X syndrome. The high conservation of the glutamate binding site across the mGlu subtypes, however, coupled with the poor pharmacokinetic properties of amino acid-type ligands that bind to the orthosteric glutamate site have made it it difficult to develop highly selective activators and antagonists of these receptors. We have taken the approach of searching for allosteric modulators of these receptors using high throughput screening (HTS) and chemical optimization approaches. We have now performed highly successful HTS programs to search for positive allosteric modulators (PAMs) of mGlu4 (for treatment of Parkinson’s disease) and both positive and negative allosteric modulators of mGlu5 (for schizophrenia and Fragile X syndrome, respectively). This presentation will focus on our integrated molecular pharmacology, chemistry, pharmacokinetic, and behavioral pharmacology studies for mGlu4 PAMs and mGlu5 NAMs, specifically. We are now making significant progress in using technology-enabled medicinal chemistry approaches to optimize these compounds as useful in vivo tools and as potential drug leads. These exciting findings suggest that allosteric modulators of the mGlus may provide a viable approach to be explored in numerous CNS disorders. Supported by NIH, the Michael J. Fox Foundation, and Seaside Therapeutics.
Discovery of a Novel Series Of Selective Mglur5 Negative Allosteric Modulators
Jean-Philippe Rocher, Ph.D, Addex Pharma SA
Allosteric modulators of glutamatergic receptors and in particular mGluR5 receptors have emerged as a novel and highly desirable class of compounds for the treatment of various CNS disorders. We have identified a new series of heterocycloalkyl-ethynyl-pyridines as potent and highly selective mGluR5 receptor Negative Allosteric Modulators (NAM). Structural differences with the MPEP type ligands are highlighted in the presentation. We will present the multiparametric optimization of the initial hit which ended in the selection of potential clinical candidates combining the best pharmacophoric features. We will describe the pharmacological properties including the results of in-vivo efficacy in rodent behavioral models of a molecule from this series, ADX48621 which has completed Phase I clinical development and is expected to start Phase IIa proof of concept studies in Parkinson's disease levodopa induced dyskinesia (PD-LID) end of 2010.
Additional abstracts coming soon
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