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Title page for ETD etd-03012016-113339


Type of Document Dissertation
Author Ennis, Elizabeth Ann
URN etd-03012016-113339
Title Identification and Characterization of Novel Inhibitors of the Presynaptic, Hemicholinium-3-Sensitive Choline Transporter
Degree PhD
Department Pharmacology
Advisory Committee
Advisor Name Title
Kevin Currie Committee Chair
Craig Lindsley Committee Member
David Robertson Committee Member
Eric Delpire Committee Member
Randy Blakely Committee Member
Keywords
  • Choline
  • Drug discovery
  • anticholinergic
  • Transporter
  • Acetylcholine
Date of Defense 2016-02-12
Availability unrestricted
Abstract
Acetylcholine controls or modulates virtually every physiological process from the regulation of skeletal and smooth muscle contraction, to learning and memory (Sellers & Chess-Williams, 2012). Consequently, alterations in cholinergic signaling underlie or impact risk for a wide variety of disorders (Berry et al., 2014) and, in some cases, afford opportunities for pharmacological intervention. The high affinity choline transporter (CHT) is a protein critical to cholinergic signaling, as it is the rate-limiting step in the synthesis of acetylcholine, and provides a unique opportunity to modulate cholinergic signaling. Until recently, hemicholinium-3 (HC-3) was the only commonly used small molecule known to directly target CHT. Unfortunately, HC-3 displays poor blood brain barrier penetration and is extremely lethal, limiting its use as a therapeutic or an in vivo tool. The identification of a novel CHT pharmacology was the goal of my thesis research which initiated a high-throughput screening effort and resulted in the discovery of ML352, a specific CHT inhibitor. The unique properties of ML352 raise the possibility of advancing cholinergic biology research.
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