%A Choudhary,Parul %A Armstrong,Emma J. %A Jorgensen,Csilla C. %A Piotrowski,Mary %A Barthmes,Maria %A Torella,Rubben %A Johnston,Sarah E. %A Maruyama,Yuya %A Janiszewski,John S. %A Storer,R. Ian %A Skerratt,Sarah E. %A Benn,Caroline L. %D 2017 %J Frontiers in Molecular Neuroscience %C %F %G English %K Acetylcholine,Solute carrier,SLC5A7,SSM electrophysiology,phenotypic screening,Mass Spectrometry,HACU,High affinity choline uptake %Q %R 10.3389/fnmol.2017.00040 %W %L %M %P %7 %8 2017-February-27 %9 Original Research %+ Dr Caroline L. Benn,Pfizer,Neusentis, Cambridge, UK,clbenn@gmail.com %# %! Increasing CHT mediated transport %* %< %T Discovery of Compounds that Positively Modulate the High Affinity Choline Transporter %U https://www.frontiersin.org/articles/10.3389/fnmol.2017.00040 %V 10 %0 JOURNAL ARTICLE %@ 1662-5099 %X Cholinergic hypofunction is associated with decreased attention and cognitive deficits in the central nervous system in addition to compromised motor function. Consequently, stimulation of cholinergic neurotransmission is a rational therapeutic approach for the potential treatment of a variety of neurological conditions. High affinity choline uptake (HACU) into acetylcholine (ACh)-synthesizing neurons is critically mediated by the sodium- and pH-dependent high-affinity choline transporter (CHT, encoded by the SLC5A7 gene). This transporter is comparatively well-characterized but otherwise unexplored as a potential drug target. We therefore sought to identify small molecules that would enable testing of the hypothesis that positive modulation of CHT mediated transport would enhance activity-dependent cholinergic signaling. We utilized existing and novel screening techniques for their ability to reveal both positive and negative modulation of CHT using literature tools. A screening campaign was initiated with a bespoke compound library comprising both the Pfizer Chemogenomic Library (CGL) of 2,753 molecules designed specifically to help enable the elucidation of new mechanisms in phenotypic screens and 887 compounds from a virtual screening campaign to select molecules with field-based similarities to reported negative and positive allosteric modulators. We identified a number of previously unknown active and structurally distinct molecules that could be used as tools to further explore CHT biology or as a starting point for further medicinal chemistry.