title: Discovery of Compounds that Positively Modulate the High Affinity Choline Transporter.
abstract: 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 theSLC5A7gene). 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.
authors.affiliation: Pfizer Neusentis, Cambridge, UK.
authors.forename: Parul
authors.initials: P
authors.lastname: Choudhary
authors.affiliation: Pfizer Neusentis, Cambridge, UK.
authors.forename: Emma J
authors.initials: EJ
authors.lastname: Armstrong
authors.affiliation: Primary Pharmacology Group, Pfizer Inc. Groton, CT, USA.
authors.forename: Csilla C
authors.initials: CC
authors.lastname: Jorgensen
authors.affiliation: Primary Pharmacology Group, Pfizer Inc. Groton, CT, USA.
authors.forename: Mary
authors.initials: M
authors.lastname: Piotrowski
authors.affiliation: Nanion Technologies Munich, Germany.
authors.forename: Maria
authors.initials: M
authors.lastname: Barthmes
authors.affiliation: Pfizer, Worldwide Medicinal Chemistry Cambridge, UK.
authors.forename: Rubben
authors.initials: R
authors.lastname: Torella
authors.affiliation: Pfizer Neusentis, Cambridge, UK.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Johnston
authors.affiliation: Central Research Laboratory, Kissei Pharmaceutical Co., Ltd. Nagano, Japan.
authors.forename: Yuya
authors.initials: Y
authors.lastname: Maruyama
authors.affiliation: Primary Pharmacology Group, Pfizer Inc. Groton, CT, USA.
authors.forename: John S
authors.initials: JS
authors.lastname: Janiszewski
authors.affiliation: Pfizer, Worldwide Medicinal Chemistry Cambridge, UK.
authors.forename: R Ian
authors.initials: RI
authors.lastname: Storer
authors.affiliation: Pfizer, Worldwide Medicinal Chemistry Cambridge, UK.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Skerratt
authors.affiliation: Pfizer Neusentis, Cambridge, UK.
authors.forename: Caroline L
authors.initials: CL
authors.lastname: Benn
keywords: HACU (high affinity choline uptake); SLC5A7; SSM electrophysiology; acetylcholine; mass spectrometry; phenotypic screening; small molecule screening; solute carrier