There exist five subtypes of the muscarinic acetylcholine receptor (M1-M5), which are differentially expressed throughout the body and play important roles in numerous physiological processes, including autonomic functions, motor control, cognition, reward, and sleep, among others. A historic lack of small molecules possessing high subtype-selectivity has hampered basic neurobiological research into the roles of each subtype in the central nervous system and has precluded successful therapeutic development of muscarinic ligands targeting a particular receptor subtype. Functional cell-based screening in conjunction with medicinal chemistry techniques were performed in order to discover highly subtype-selective allosteric ligands for M1, M4, and M5. Multiple series of M1 positive allosteric modulators, M1 allosteric agonists, M1 antagonists, M4 positive allosteric modulators, and the first series of selective M5 positive allosteric modulators were successfully discovered, optimized, and characterized.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-09202010-221417 |
| Date | 21 September 2010 |
| Creators | Bridges, Thomas Miller |
| Contributors | Craig Lindsley, Jeffrey Conn, Vsevolod Gurevich, Aaron Bowman |
| Publisher | VANDERBILT |
| Source Sets | Vanderbilt University Theses |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.vanderbilt.edu/available/etd-09202010-221417/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to Vanderbilt University or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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