Acetylcholine (ACh) is a major neurotransmitter that modulates multiple biological processes including periphereal (cardiovascular) and central nervous system (motor function, attention disorders and addiction).  A major course of research has been targeted at potentiation of the cholinergic signaling through the use of acetylcholinesterase inhibitors (AChE) � which is the predominant course of treatment strategy for Alzheimer's disease (AD).  Another unexplored therapeutic target is the high-affinity choline transporter, which is presynaptic and could lead to the development of novel tool compounds with which to further explore these cholinergic pathways.  Unfortunately, the only small molecule available that targets CHT is hemicholinium-3, a quaternary ammonium containing molecule, making this less than ideal as a tool compound.  In order to identify more appropriate small molecule inhibitors, we utilized a high-throughput screening (HTS) campaign followed by an iterative medicinal chemistry approach.  Through this, we discovered ML352 which shows nanomolar inhibition at both high (10 mM) and low (100 nM) concentrations of applied choline, 290 nM and 90 nM, respectively.  The discovery of this molecule should enable further investigation of the cholinergic pathways.

Discovery and structure-activity relationship of a novel choline transporter inhibitor (ML352)

246th National Meeting (2013)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.