2009 |
Conn, Jeffrey P |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Functional Effects of Mglur Potentiators in the Cns
DESCRIPTION (provided by applicant): Animal and clinical studies suggest that agonists of group II metabotropic glutamate (mGlu) receptors (mGlu2 and mGlu3) could provide a novel approach for the treatment of anxiety disorders and schizophrenia. However, group II mGlu receptor agonists activate both mGlu2 and mGlu3, and the relative contributions of these two receptor subtypes to the actions of these drugs are not known. Thus, there is a critical need to determine whether activation of a specific group II mGlu receptor subtype (mGlu2 or mGlu3) could elicit the behavioral and electrophysiological effects of group II mGlu receptor agonists that are relevant to their potential therapeutic efficacy. Furthermore, development of tolerance and adverse effects of direct agonists could limit their clinical use. Thus, it will be important to develop novel approaches to increasing activity of these receptors that may have advantages relative to direct agonists. In recent months, a novel class of compounds has been discovered that act as selective allosteric potentiators of the mGlu2 receptor subtype. These compounds do not activate mGlu2 directly but act at an allosteric site to potentiate glutamate-induced activation of the receptor. These compounds represent the first clear departure from glutamate analogs as mGlu2 activators are the first compounds that are highly selective for mGlu2 relative to mGlu3 or other mGlu receptor subtypes. However, the functional effects of these compounds in systems relevant to the therapeutic efficacy of group II mGlu receptor agonists have not been determined. We propose a series of studies in which we will determine the effects of allosteric potentiators of mGlu2 on electrophysiological responses to group II mGlu receptor activation in cell populations that have been postulated to be important for the therapeutic effects of these compounds. In addition, we will systematically evaluate the behavioral effects of allosteric mGlu2 potentiators in animal models predictive of anxiolytic and antipsychotic activity. Finally, we will determine whether direct agonists and allosteric potentiators differ in their propensity to induce desensitization and behavioral tolerance after chronic administration. These studies will build on the exciting advances suggesting a potential therapeutic utility of group II mGlu receptor activators and could provide a novel approach to increasing activity of these receptors that for development of new therapeutic agents.
|
1 |
2009 |
Conn, Jeffrey P |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Muscarinic Receptor Activators as Novel Antipsychotic Agents
DESCRIPTION (provided by applicant): Recent clinical studies reveal that agents that activate muscarinic acetylcholine receptors (mAChRs) have robust efficacy in reducing psychotic symptoms in patients with schizophrenia as well as AD and other neurodegenerative disorders. Evidence suggests that the antipsychotic effects of cholinergic agents may be mediated by the M1 mAChR subtype. However, previous compounds developed to selectively activate M1 receptors lack true specificity for M1. This has resulted in problems with adverse effects due to M2 and M3 activation in patients and has made it impossible to definitively determine whether the behavioral and clinical effects of these compounds are mediated by M1 or other mAChR subtypes. Despite major efforts by multiple industry and academic laboratories, it has been impossible to develop clinically useful highly selective M1 agonists that act the orthosteric acetylcholine (ACh) binding site. This is likely due to the high degree of conservation of the ACh site between mAChR subtypes. In recent years we have been highly successful in establishing a new class of compounds that act as allosteric potentiators of G protein-coupled receptors that may provide key advantages to direct-acting agonists. Unlike agonists, these compounds do not directly activate the receptor but act at an allosteric site to potentiate the response to the endogenous agonist. In general, these compounds tend to be more selective for the intended receptor because they do not interact with the highly conserved neurotransmitter binding site. Another major breakthrough occurred when other laboratories discovered a novel class of M1 agonists that interact with an ectopic site on the receptor rather than the ACh binding site. Unlike traditional agonists, these compounds are highly specific for M1 relative to other mAChR subtypes and provide exciting new tools to definitively determine whether the physiological and behavioral effects of mAChR agonists thought to be important for antipsychotic activity are mediated by M1. In the proposed studies, we will take advantage of automated technologies and a high throughput screen for allosteric potentiators of M1 that we have developed to identify novel compounds that act as highly selective allosteric potentiators of this receptor. In addition, we will use these compounds along with the new selective ectopic site M1 agonists, a novel M4 allosteric potentiator and a panel of mice in which specific mAChR subtypes have been deleted to test the hypothesis that the antipsychotic-like profile of muscarinic agonists is mediated by M1 and to determine whether allosteric potentiators of M1 have electrophysiological and behavioral effects that are similar to those of M1 agonists.
|
1 |
2009 |
Conn, Jeffrey P |
P30Activity Code Description: To support shared resources and facilities for categorical research by a number of investigators from different disciplines who provide a multidisciplinary approach to a joint research effort or from the same discipline who focus on a common research problem. The core grant is integrated with the center's component projects or program projects, though funded independently from them. This support, by providing more accessible resources, is expected to assure a greater productivity than from the separate projects and program projects. |
Recruitment of in Vivo Neuropharmacologist to Support Cns Drug Discovery Research
DESCRIPTION (provided by applicant): The Vanderbilt Program in Drug Discovery (VPDD) is a world class effort fully focused on discovery and characterization of novel molecules to evaluate new potential treatment strategies for CNS disorders. The VPDD has had tremendous success in discovery of multiple ligands for CNS neurotransmitter receptors, ion channels, and other signaling proteins. This provides an exciting opportunity to realize unprecedented advances in understanding of the impact of manipulating these signaling pathways on animal behavior and the potential therapeutic utility of drugs acting on these systems. However, it is critical that molecules generated from this and similar academic drug discovery efforts are fully characterized in terms of pharmacokinetic properties and brain penetration before using novel molecules for in vivo studies. Thus, in vivo neuropharmacologists working with newly discovered compounds must seamlessly incorporate studies of drug disposition into their work. VPDD has established state of the art facilities for animal dosing, plasma and csf collection, and analytical chemistry required for detailed pharmacokinetic studies of novel compounds in animal models. In addition both the VPDD and Vanderbilt's Center for Molecular Neuroscience (CMN) have established outstanding facilities for use in behavioral and other in vivo studies in rodent models. This provides the opportunity to move beyond cellular and molecular studies that drive many of the current VPDD efforts and focus on gaining new insights into in vivo effects of manipulating specific neurotransmitter systems and signaling pathways. However, to take advantage of this unique opportunity, it will be critical to recruit faculty who have strong in vivo pharmacology expertise and who have the skills required to combine behavioral pharmacology with studies of drug disposition and CNS exposure of novel compounds. We now seek funding through the NIH to support recruitment of an outstanding in vivo neuropharmacologist to a tenure track faculty position in VPDD and Department of Pharmacology, we propose a strong development package to the new faculty recruit and provide a clear plan to work with new recruit to through faculty mentoring, collaborative research opportunities, and other support needed to allow the new recruit to establish an independent career and leadership position in neuropharmacology. PUBLIC HEALTH RELEVANCE: We propose recruitment of an outstanding in vivo neuropharmacologist to a tenure track faculty position in the Vanderbilt Program in Drug Discovery and the Vanderbilt Department of Pharmacology. Working within the context of the VPDD, provides a unique opportunity for an in vivo neuropharmacologist to achieve unprecedented advances in understanding of the impact of manipulating specific signaling pathways on animal behavior and the potential therapeutic utility of drugs acting on these systems. Using support from this grant, we will provide strong development package, focused faculty mentoring, collaborative research opportunities, and other support needed to help the new recruit to establish an independent career and leadership position in neuropharmacology.
|
1 |
2009 |
Conn, Jeffrey P |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Regulation of Signaling by Mglur5
DESCRIPTION (provided by applicant): A large number of anatomical, cellular, molecular, and behavioral studies have led to the hypothesis that selective activators of mGluRS may have exciting potential as novel antipsychotic and cognition-enhancing agents. While these studies represent a major advance in our understanding of mGluRS function, selective agonists of mGluRS have not been available to directly test this hypothesis in vivo. Unfortunately, it has been difficult to develop compounds that act as selective agonists of specific mGluR subtypes that have properties that are suitable for in vivo studies or ultimate development of therapeutic agents. Over the past year, we made a major breakthrough in developing a novel approach to activation of mGluRS using selective allosteric potentiators of this receptor. These compounds do not activate mGluR5 directly but dramatically potentiate the response of the receptor to glutamate. These allosteric potentiators offer high selectivity for mGluRS and provide an exciting new approach to development of novel selective activators of G protein-coupled receptor (GPCR) subtypes. One of these compounds, termed CDPPB, is systemically active, has a relatively long half life and readily crosses the blood brain barrier. This provides an unprecedented opportunity to determine the electrophysiological and behavioral effects of selective mGluRS potentiators. Furthermore, defining the precise domains of the receptors required for this action and the mechanisms involved in allosteric potentiation of mGluRs by CDPPB and its analogs will be important for further development of this approach to mGluR activation. We now propose a series of molecular, structure function, and pharmacological studies to rigorously test the hypothesis that potentiation of mGluRS responses by CDPPB and its analogs is mediated by binding to an allosteric binding site on mGluRS that also binds to allosteric antagonists of this receptor, such as MPEP. In addition, we will determine the electrophysiological effects of CDPPB on activation of mGluRS by exogenous agonists and stimulation of glutamatergic afferents in systems that may be important for potential antipsychotic and cognition-enhancing effects of this compound. Finally, we will determine the behavioral effects of CDPPB in animal models that have been used to assess potential antipsychotic and cognition-enhancing activity of novel agents. These studies will have a major impact on our understanding of mGluRS function and an exciting new approach to activation of this receptor with allosteric potentiators. In addition, these studies will have a major impact on thinking about the utility of allosteric potentiators for multiple other GPCRs where development of direct agonists has been problematic.
|
1 |