Structure–Activity Relationship Studies of N-Methylated and N-Hydroxylated Spider Polyamine Toxins as Inhibitors of Ionotropic Glutamate Receptors

Abstract

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 N-methyl and N-hydroxy functionalities. Here, we investigate the effect of both N-methylation and N-hydroxylation of spider polyamine toxins by the synthesis and biological evaluation of the naturally occurring N-methylated argiopinines and pseudoargiopinines I and II, N-hydroxylated Agel-489 and Agel-505, as well as N-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.

Chapter 8. Therapeutic Applications of Spider-Venom Peptides

“…Most of these compounds are non-selective, 17 but several recent studies have endeavoured to modify acylpolyamines to chemically tune their subtype preferences, with varying degrees of success. [18][19][20] Further study of spider-venom acylpolyamines may be fruitful in providing novel lead compounds that target ionotropic glutamate receptors.…”

Antimicrobial Activity of Purified Toxins from Yellow Wasp <i>Polistes flavus</i> (Vespidae) against Certain Bacteria and Fungi

“…Venom toxins of Polybia paulista showed genotoxic and mutagenic effects. Polyamine toxin from yellow wasp is potent open-channel blockers of ionotropic glutamate (IGlu) receptors that show selective ligand binding [7].…”

An iGlu Receptor Antagonist and Its Simultaneous Use with an Anticancer Drug for Cancer Therapy

“…[11] They are obtained from the venom of spiders and wasps, and are lowmolecular-weight compounds, which block the receptors by an uncompetitive mechanism. [12] As polyamine toxins are selective inhibitors of Ca 2 + permeable glutamate receptors, [13] they are effective anticonvulsants in animal seizure models and show important functions in polytherapies [14] . In recent years, there has been a growing trend in the usage of glutamate receptor antagonists for the treatment of cancer.…”