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Title page for ETD etd-12112013-231032

Type of Document Master's Thesis
Author Bates, Brittney Shaye
URN etd-12112013-231032
Title Synthesis and Optimization of a Model System Representing the Natural Product Marineosin A and Discovery of VU0431316, a Negative Allosteric Modulator of the Metabotropic Glutamate Receptor 5
Degree Master of Science
Department Chemical and Physical Biology
Advisory Committee
Advisor Name Title
Craig W. Lindsley Committee Member
Gary A. Sulikowski Committee Member
Stephen W. Fesik Committee Member
  • marineosin
  • total synthesis
  • model system
  • mGluR
  • allosteric modulator
Date of Defense 2013-12-19
Availability unrestricted
Marineosin A was isolated from a marine sediment-derived actinomycete in 2008. The intriguing biological activity and novel chemical structure warranted completion of the total synthesis of this compound. The model systems described herein were created as tools to develop chemistry and test the viability of proposed synthetic routes toward marineosin A. Moreover, the model systems were tested as possible minimal pharmacophores that would greatly simplify SAR studies around the biologically active natural product.

Metabotropic glutamate receptor 5 (mGluR5) is involved in a variety of psychiatric and neurologic disorders, and mGluR5 therapeutics have the potential to dramatically improve the treatments available for these disorders. Because conventional orthosteric modulators of mGluR5 can lack satisfactory aqueous solubility, demonstrate poor oral bioavailability, and/or exhibit unfavorable effects, there is a need for selective allosteric modulators of mGluR5 that overcome these deficiencies. While MPEP and MTEP have proven to be valuable negative allosteric modulator (NAM) tool compounds, both of these compounds have characteristics that prevent them from becoming full therapeutic molecules. Thus, there has been an interest in the development of mGluR5 NAMs within chemotypes that do not contain a disubstituted alkyne motif. The following describes the successful discovery of tool compound VU0431316 from an aryl ether series of mGluR5 NAMs.

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