Design, synthesis, and pharmacological characterization of polyamine toxin derivatives: Potent ligands for the pore-forming region of AMPA receptors

Polyamine toxins, such as philonthotoxins, are low-molecular-weight compounds isolated from spiders and wasps, which modulate ligand-gated ion channels in the nervous system. Philanthotoxins bind to the pore-forming region of AMPA receptors, a subtype of glutomate receptors which are important for memory formation and ore involved in neurodegenerative diseases. Previous studies hove demonstrated that modification of the polyamine moiety of philanthotoxins can lead to very potent and highly selective ligands for the AMPA receptor, as exemplified with philanthotoxin-56. Much less attention has been paid to the importance of the aromatic head group of philanthotoxins, but herein we demonstrate that modification of this moiety leads to a significant improvement in potency relative to philanthotoxin-56 at cloned AMPA receptors. Interestingly, the incorporation of an adamantane moiety is particularly favorable, and the most potent compound has a K, value of 2 nm, making it the most potent uncompetitive antagonist of AMPA receptors described to date. Such compounds are potentially useful as neuroprotective agents.