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    Identification and Characterization of Novel Inhibitors of the Presynaptic, Hemicholinium-3-Sensitive Choline Transporter

    Ennis, Elizabeth Ann
    : https://etd.library.vanderbilt.edu/etd-03012016-113339
    http://hdl.handle.net/1803/10650
    : 2016-03-01

    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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