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  • Addiction, Drugs
  • Information from Lay-Language Summaries is Embargoed Until the Conclusion of the Scientific Presentation

    614—Metabotropic Glutamate Receptors: Pharmacology and Physiology

    Tuesday, November 12, 2013, 1:00 pm - 5:00 pm

    614.06: Allosteric modulators of muscarinic acetylcholine and metabotropic glutamatergic receptors as promising therapeutic strategies for cognition enhancement in Alzheimer’s disease

    Location: Halls B-H

    *J. M. ROOK, A. G. WALKER, Q. HUAN, S. R. STAUFFER, C. M. NISWENDER, J. S. DANIELS, C. K. JONES, C. W. LINDSLEY, P. J. CONN;
    Dept. of Pharmacol. and Vanderbilt Ctr. for Neurosci. Drug Discovery, Vanderbilt Univ. Med. Ctr., Nashville, TN

    Abstract Body: A large number of cellular and behavioral studies suggest that selective activation of specific G protein-coupled receptor (GPCR) subtypes could provide a novel approach for treatment of multiple neurological disorders. Most notably, selective activation of metabotropic glutamate receptor subtype 5 (mGlu5) and muscarinic receptor subtypes 1 and 4 (M1 and M4) could provide a novel approach for the treatment of schizophrenia, as well as enhance cognition in disease states such as schizophrenia and Alzheimer’s disease (AD). Unfortunately, it has been difficult to develop compounds that act as selective orthosteric agonists of individual GPCR subtypes that have properties likely to be suitable for development of therapeutic agents. A major breakthrough that allowed GPCR selective activators to emerge as a viable approach was the discovery of highly selective positive allosteric modulators (PAMs) of these receptors. As opposed to direct activation of the GPCR, PAMs dramatically potentiate the response of the receptor to its endogenous ligand glutamate. In addition to offering high subtype selectivity, this unique property of PAMs theoretically could provide therapeutic advantages by maintaining the normal temporal and spatial requirements of receptor activation by natural agonists. One of the most exciting aspects of targeting mGlu5 and M1/M4 for treatment of AD is that PAMs of these receptors could potentially treat not only the cognitive symptoms that are the hallmark of the disease but also the psychosis that is present in a large percent of AD patients. Preclinical behavioral studies in rodent models of AD reveal that these compounds have robust effects in animal models that have been used to predict efficacy of novel antipsychotic agents. In addition to potential therapeutic efficacy in treatment of psychosis, these data demonstrate the in vivo efficacy of novel PAMs in multiple rodent behavioral models cognition enhancement. These studies provide evidence suggesting that these compounds may also be useful for improving cognitive function in patients with age-related dementia and AD.

    Lay Language Summary: Research from The Vanderbilt Center for Neuroscience Drug Discovery indicates that increasing the activity of specific receptors within the brain could provide a promising new treatment strategy to enhance learning and memory in individuals suffering from Alzheimer’s disease.
    Alzheimer’s disease is the most frequently observed cause of dementia and age-related cognitive decline and is marked by deficits in learning and memory, as well as thinking and reasoning skills. More the 5 million Americans are living with Alzheimer’s disease and 1 in 3 seniors will die from the disease or another form of dementia. In 2013, it is projected that Alzheimer’s disease will cost the United States $203 billion. As the number of elderly within the population continues to increase, these numbers will grow exponentially. Currently, there is no cure for Alzheimer’s disease and the existing medications only temporarily slow the progression of the disease. Therefore, there is a clear need to discover new treatment strategies to help stop the advancement of symptoms and improve the quality of life for those with Alzheimer’s disease.
    Glutamate and acetylcholine are two chemicals within the brain essential for normal cognitive function and have been shown to have reduced levels in the brains of Alzheimer’s patients. Accumulating evidence suggests that selective activation of specific glutamate (metabotropic glutamate receptor subtype 5) and acetylcholine (muscarinic receptor subtypes 1 and 4) receptors in the brain could provide a novel approach for the treatment of deficits in cognition in both Alzheimer’s disease and schizophrenia. One of the most exciting aspects of targeting these receptors for treatment of Alzheimer’s disease is that activators of these receptors not only have the potential to improve the cognitive symptoms that are the hallmark of the disease but also the psychosis that is present in a large percent of late stage Alzheimer’s disease patients. Previous discovery efforts to develop new potential drug candidates capable of selectively activating individual receptors in the brain have failed. However, a major breakthrough has emerged as a viable approach to develop highly selective activators of these receptors. This approach enhances the activity of natural chemicals within the brain at targets which may be diminished in Alzheimer’s and schizophrenia patients, avoiding many unwanted side effects associated with direct activation by a drug. Researchers in the Vanderbilt Center for Neuroscience Drug Discovery have been highly successful at developing new compounds that selectively activate these receptors and possess excellent properties to determine whether they enhance learning and memory in preclinical models of Alzheimer’s disease.
    To test this hypothesis, we assessed the ability of our novel compounds to enhance learning and memory in preclinical animal models. Preclinical studies in rodent models of Alzheimer’s disease reveal that these novel compounds have robust effects in behavioral models that predict antipsychotic activity. In addition to potential therapeutic benefit in the treatment of psychosis, our research demonstrates the beneficial effects of our novel compounds in multiple rodent behavioral models of learning and memory. These studies provide direct evidence suggesting that these compounds have exciting potential to improve cognitive function in patients with age-related dementia and Alzheimer’s disease.