The essential roles of glutamatergic signaling in both normal and impaired cognitive functioning have caused metabotropic glutamate (mGlu) receptors to become targets of interest for the treatment of psychiatric disorders. The eight mGlu receptors are G-protein coupled receptors, which have been placed into three groups based on their sequence homology and preferred signaling pathway. Studies of the group II receptors, mGlu2 and mGlu3, have been limited by a lack of selective ligands. We used iterative, parallel, multidimensional synthesis along with pharmacologic and pharmacokinetic analyses to develop novel allosteric modulators for these targets, which act at a distinct site from where the endogenous ligand glutamate binds. These efforts led to the development of the first reported selective mGlu3 negative allosteric modulator (NAM), a series of dual mGlu2/3 NAMs, and provided the first characterization of a selective mGlu2 NAM. These compounds were then used in a series of electrophysiological and behavioral studies to reveal an unexpected role for postsynaptic mGlu3 receptors in the development of long term depression (LTD) of synaptic firing in the medial prefrontal cortex and implicate mGlu3 dysfunction as a potential cause for persistence of cued memories. Second generation mGlu2 and mGlu3 selective NAMs were then used in rodent models of depression and anxiety, reveal a potential antidepressant effect of mGlu3 NAMs. Finally, we used a candidate gene approach to look at the distribution of variants in the genes encoding for mGlu receptors in substance dependent patients and in matched controls, which uncovered a possible correlation of structural variance in mGlu1, mGlu2, and mGlu3 receptors with the development of substance dependence.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-07102015-131401 |
| Date | 15 July 2015 |
| Creators | Wenthur, Cody James |
| Contributors | Craig Lindsley, Randy Blakely, Aaron Bowman, Joey Barnett, P. Jeffrey Conn |
| 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-07102015-131401/ |
| Rights | restricted, 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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