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Title page for ETD etd-12112011-145832


Type of Document Master's Thesis
Author Le, Uyen Mai
Author's Email Address uyen.m.le@vanderbilt.edu
URN etd-12112011-145832
Title Optimization and characterization of muscarinic acetylcholine receptor M4 positive allosteric modulators
Degree Master of Science
Department Chemical and Physical Biology
Advisory Committee
Advisor Name Title
Craig Lindsley Committee Member
Gary Sulikowski Committee Member
P. Jeffrey Conn Committee Member
Keywords
  • positive allosteric modulator
  • M4 PAM
  • muscarinic acetylcholine receptor
  • mAChR
Date of Defense 2011-11-30
Availability unrestricted
Abstract
Acetycholine is one of the major neurotransmitters that regulate various functions ranging from cognition to motor. It activates muscarinic acetylcholine receptors (mAChRs), which are highly expressed in the brain. mAChRs are implicated in many physiological processes and neurological disorders; therefore, these receptors are appealing targets for the regulation of acetylcholine functions. Due to high structural homology across the five mAChR subtypes, developing tool compounds that are subtype selectivity is cumbersome. We are interested in enhancing selectivity and receptor activity of the muscarinic acetylcholine receptor subtype M4 by positive allosteric modulation (PAM). Because positive allosteric modulators mimic basal response and are only efficacious in the presence of the endogenous agonist, they have lower off-target toxicity and allow for higher subtype selectivity. Using iterative parallel library synthesis, we improve specificity, potency, and pharmacology profile of our recently published M4 PAM, VU0152100.
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