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Development of novel, cns penetrant mglu3 selective negative allosteric modulator probes derived from a closely related mglu5 positive allosteric modulator

dc.creatorBruner, Joshua Andrew
dc.date.accessioned2020-08-22T00:02:57Z
dc.date.available2012-04-10
dc.date.issued2012-04-10
dc.identifier.urihttps://etd.library.vanderbilt.edu/etd-03262012-165154
dc.identifier.urihttp://hdl.handle.net/1803/11422
dc.description.abstractMetabotropic 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.
dc.format.mimetypeapplication/pdf
dc.subjectnegative allosteric modulator
dc.subjectmGlu3
dc.titleDevelopment of novel, cns penetrant mglu3 selective negative allosteric modulator probes derived from a closely related mglu5 positive allosteric modulator
dc.typethesis
dc.contributor.committeeMemberGary Sulikowski
dc.type.materialtext
thesis.degree.nameMS
thesis.degree.levelthesis
thesis.degree.disciplineChemistry
thesis.degree.grantorVanderbilt University
local.embargo.terms2012-04-10
local.embargo.lift2012-04-10
dc.contributor.committeeChairCraig Lindsley


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