Neuromodulating Alkaloids from Millipede Defensive Secretions

Natural products are commonly deployed as defensive agents and these molecules have formed the basis for today’s therapeutic agents. Millipedes have evolved specialized glands to store structurally diverse chemical defenses, including cyanide containing metabolites, alkaloids, and oxidized aromatics. A study into the excretions of an understudied millipede, Ischnocybe plicata, led to characterizing four new oxidized alkaloids (ischnocybines) with potent and selective binding affinity for sigma-1, an orphan neuroreceptor. Analysis by MS and 2D NMR revealed the relative configurations of these four ischnocybines. These molecules are structurally distinct from all other millipede metabolites and are the first metabolites to be shown to bind to a specific neuroreceptor with low nanomolar affinity (Ki 13.6 nM). In addition, this natural structural diversity establishes a structure activity relationship and supports a proposed biosynthetic pathway leading to the target compounds.