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Title page for ETD etd-03262012-165154


Type of Document Master's Thesis
Author Bruner, Joshua Andrew
Author's Email Address joshua.a.bruner@vanderbilt.edu
URN etd-03262012-165154
Title Development of novel, cns penetrant mglu3 selective negative allosteric modulator probes derived from a closely related mglu5 positive allosteric modulator
Degree Master of Science
Department Chemistry
Advisory Committee
Advisor Name Title
Craig Lindsley Committee Chair
Gary Sulikowski Committee Member
Keywords
  • negative allosteric modulator
  • mGlu3
Date of Defense 2012-03-23
Availability unrestricted
Abstract
Metabotropic glutamate (mGlu) receptors are examples of family C G-protein-coupled receptors that possess vast roles in the pathophysiology of central nervous system (CNS) disorders. In order to fully understand the mGlu receptors’ roles in disease, it is necessary to develop potent and highly selective probes to individually target the mGlu receptor subtypes. At the outset of this project, there existed no suitable probes to selectively target metabotropic glutamate receptor 3 (mGlu3). Herein we report the discovery and SAR of a novel mGlu3 negative allosteric modulator (NAM) probe (VU0463597) with modest selectivity (~5- to 15-fold) versus fellow group II mGlu receptor, mGlu2. The mGlu3 NAM was discovered via a ‘molecular switch’ from a closely related, potent mGlu5 positive allosteric modulator (PAM), VU0092273. This mGlu3 NAM (VU0463597) displays an IC50 value of 649 nM and is inactive on mGlu5.
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