General synthesis of β-alanine-containing spider polyamine toxins and discovery of Nephila polyamine toxins 1 and 8 as highly potent inhibitors of ionotropic glutamate receptors

摘要

Certain spiders contain large pools of polyamine toxins, which are putative pharmacological tools awaiting further discovery. Here we present a general synthesis strategy for this class of toxins and prepare five structurally varied polyamine toxins. Electrophysiological testing at three ionotropic glutamate receptor subtypes reveals that two of these, Nephila polyamine toxins 1 (NPTX-1) and 8 (NPTX-8), comprise intriguing pharmacological activities by having subnanomolar IC_50 values at kainate receptors.