title: Structure-activity relationship study of spider polyamine toxins as inhibitors of ionotropic glutamate receptors.
abstract: The spider polyamine toxins Joro spider toxin-3 (JSTX-3) and Nephila polyamine toxins-1 and -8 (NPTX-1 and NPTX-8) are isolated from the venom of the orb-weaver spider Nephila clavata (Joro spider). They share a high degree of structural resemblance, their aromatic head groups being the only difference, and were recently found to be very potent open-channel blockers of ionotropic glutamate (iGlu) receptors. In this study we designed and synthesized a collection of 24 analogues of these toxins using a recently developed solid-phase synthetic methodology. Systematic variation in two regions of the toxins and subsequent evaluation of biological activity at AMPA and NMDA subtypes of iGlu receptors provided succinct information on structure-activity relationships. In particular, one set of analogues were found to display exquisite selectivity and potency for AMPA receptors relative to the natural products. Thus, this systematic SAR study has provided new pharmacological tools for studies of iGlu receptors.
authors.affiliation: Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen (Denmark).
authors.forename: Xiao-Feng
authors.initials: XF
authors.lastname: Xiong
authors.forename: Mette H
authors.initials: MH
authors.lastname: Poulsen
authors.forename: Rama A
authors.initials: RA
authors.lastname: Hussein
authors.forename: Niels G
authors.initials: NG
authors.lastname: Nørager
authors.forename: Kristian
authors.initials: K
authors.lastname: Strømgaard
mesh_terms: D000818:Animals; D007700:Kinetics; D009865:Oocytes / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D011073:Polyamines / Q000737:chemistry*; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D058468:Receptors, Ionotropic Glutamate / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics; D013111:Spider Venoms / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013112:Spiders; D013329:Structure-Activity Relationship; D014982:Xenopus laevis / Q000254:growth & development
chemical_list: C044936:JSTX spider toxin; D011073:Polyamines; D018091:Receptors, AMPA; D058468:Receptors, Ionotropic Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; D011994:Recombinant Proteins; D013111:Spider Venoms
keywords: glutamate receptors; natural products; polyamine toxins; structure-activity relationships