The neurotransmitter acetylcholine (ACh) plays a critical role in autonomic function, motor control, attention, learning, and memory, and reward. The high-affinity choline transporter (CHT) is the ratelimiting determinant of ACh synthesis, yet the transporter remains a largely undeveloped target for the detection and manipulation of synaptic cholinergic signaling. ML352 is a novel, noncompetitive inhibitor of the presynaptic choline transporter.
In vitro: At concentrations fully antagonized CHT in transfected cells and nerve terminal preparations, ML352 exhibited no inhibition of acetylcholinesterase or cholineacetyltransferase and also lacked activity at dopamine, serotonin, and norepinephrine transporters, as well as many receptors and ion channels. ML352 exhibited noncompetitive choline uptake inhibition in intact cells and reduced the apparent density of hemicholinium-3 binding sites in membrane assays, indicating allosteric transporter interactions [1].
In vivo: DMPK studies revealed a high intravenous plasma clearance, a combination of the oral bioavailability and total brain concentrations indicate ML352 to be a suitable probe for studies of altered in vivo ACh signaling and behavioral effects in rodents [2].
Clinical trial: Up to now, ML352 is still in the preclinical development stage.
Reference:
[1] Ennis EA, Wright J, Retzlaff CL, McManus OB, Lin Z, Huang X, Wu M, Li M, Daniels JS, Lindsley CW, Hopkins CR, Blakely RD. Identification and characterization of ML352: a novel, noncompetitive inhibitor of the presynaptic choline transporter. ACS Chem Neurosci. 2015 Mar 18;6(3):417-27.
[2] Elizabeth Ennis Miss, Jane Wright, James Tarr, Charles Locuson, Corey Hopkins, J Daniels, Craig Lindsley and Randy Blakely. A Novel Approach to Cholinergic Signaling Modulation: Development and Characterization of ML352, a Novel, Noncompetitive Inhibitor of the Presynaptic Choline Transporter. The FASEB Journal vol. 29 no. 1 Supplement 932.6