Structure–Activity Relationship Studies of <i>N</i>‑Methylated and <i>N</i>‑Hydroxylated Spider Polyamine Toxins as Inhibitors of Ionotropic Glutamate Receptors

Polyamine toxins from spiders and wasps are potent open-channel blockers of ionotropic glutamate (iGlu) receptors. It is well-established that secondary amino groups in the polyamine moiety of these toxins are key to both selectivity and potency at iGlu receptors, still some native spider polyamine toxins comprise both <i>N</i>-methyl and <i>N</i>-hydroxy functionalities. Here, we investigate the effect of both <i>N</i>-methylation and <i>N</i>-hydroxylation of spider polyamine toxins by the synthesis and biological evaluation of the naturally occurring <i>N</i>-methylated argiopinines and pseudoargiopinines I and II, <i>N</i>-hydroxylated Agel-489 and Agel-505, as well as <i>N</i>-methylated analogues of the NMDA and AMPA iGlu receptor subtype selective antagonists ArgTX-93 and ArgTX-48. Efficient synthetic strategies for the synthesis of target compounds were developed, and evaluation of biological activity at AMPA and NMDA receptors identified highly potent and in some cases very selective ligands