Synthesis and Neurobiological Characterization of Barbamide and Analogs

Abstract Marine cyanobacteria produce diverse secondary metabolites, which have biological activity on the human nervous system. We report evaluation of the cyanobacterial metabolite barbamide and analogs in the modulation of sensory neurons. We optimized synthesis of barbamide and an initial series of analogs with modifications of the trichloromethyl group to explore its role in function as well as simplify future synthetic efforts. Biological activity of this series was first evaluated using a multi-electrode array assay with human induced pluripotent stem cell nociceptors. We found that all three compounds were able to reduce neuronal firing rates in a dose-dependent manner consistent with potential use as an analgesic. Next, barbamide was further evaluated using primary human sensory neurons with whole cell patch clamp to gain insight into the mechanism driving the reduction in neuronal firing rate. We found that barbamide significantly decreased spontaneous and evoked action-potential firing in these neurons without overt toxicity. Finally, we evaluated the impact of barbamide on neurite outgrowth using PC12 cells and primary mouse dorsal root ganglia. We found that barbamide and trifluoromethyl barbamide increased neurite outgrowth. Together, this combination of effects further establishes the potential of the barbamide scaffold for the development of therapeutics focused on neuronal function/dysfunction.