The Characterization of wact-45, a Novel Small Molecule Tool that Likely Inhibits the Vesicular Acetylcholine Transporter

Abstract

Small molecule modulators of nervous system function can have utility as therapeutics or as research tools. Thus, the discovery of novel neuromodulators can be of great benefit. Using C. elegans as a model to identify neuroactive compounds, we have uncovered 82 molecules that modulate the egg-laying rate of worms. To assist the characterization of their mechanism of action, I investigated the locomotor phenotypes induced by these compounds. This identified wact-45, a compound that induces a coiler phenotype in worms reminiscent of cholinergic reduction-of-function mutants. Several lines of evidence suggest that wact-45 inhibits the vesicular acetylcholine transporter (VAChT). Notably, wact-45 suppresses the paralysis induced by the acetylcholinesterase inhibitor aldicarb, and mutants that resist the effect of the VAChT inhibitor vesamicol also resist the effects of wact-45. Its potent activity in nematodes and zebrafish suggests that wact-45 has utility as a tool to probe VAChT function in a broad range of species.