New Molecules for Understanding and Treating Diseases of the Central Nervous System
Brain cells have a receptor on their surface called the M1 muscarinic acetylcholine receptor that plays a role in debilitating neurodegenerative diseases such as Alzheimer’s disease and schizophrenia. Prior attempts to develop compounds other than the chemical acetycholine that exclusively target the M1 receptor have failed. The lack of alternative compounds that selectively bind the M1 receptor hampers our ability to study how the M1 receptor controls human behavior and biology and how it can be used to design new drug therapies for neurological diseases.
Vanderbilt researchers supported under the Common Fund’s Molecular Libraries and Imaging program are using high-throughput screening approaches – testing large numbers of potential drugs – to identify potential new compounds for drug therapies that specifically bind to the M1 muscarinic receptor. To be effective, promising drug candidates must penetrate cells, are potent at extremely low concentrations, and show greater than 10-fold selectivity for M1 over other receptors in the muscarinic family (M2, M3, M4 and M5). The researchers have identified two promising compounds that selectively activate the M1 receptor and can reverse learning deficits in test rodents with few adverse side effects. Discovery of new compounds that specifically activate the M1 receptor gives researchers new research tools to understand how M1 receptors function in the central nervous system and to identify new therapies for neurological disorders such as Alzheimer’s disease and schizophrenia.
Lebois EP, Bridges TM, L. Lewis M, Dawson ES, Kane AS, Jones CK, Xiang Z, Jadhav SB, Yin H, Kennedy JP, Meiler J, Niswender CM, Jones, CK, Conn JP, Weaver CD, Lindsley CW. ACS Chem. Neurosci.200; DOI: 10.1021/cn900003h. Link: http://pubs.acs.org/doi/pdfplus/10.1021/cn900003h
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