title: Arthropod toxins as leads for novel insecticides: an assessment of polyamine amides as glutamate antagonists.
abstract: In the search for new toxins, preferably with new sites of action, the polyamine amides represent a new class of compounds with potential as insecticides and as pharmaceutical agents due to their antagonism of ligand-gated cation channels. In particular, they are potent antagonists of the L-glutamate receptors of insect skeletal muscle. In this paper, we report on synthetic studies to produce hybrid analogues based upon the argiotoxin spider toxins and philanthotoxin-433 which is obtained from a solitary, parasitic wasp. We speculate upon possible modes and sites of action for these antagonists and we discuss their potential as insecticides and in the possible treatment of ischaemic damage. The synthesis and characterization of 4-hydroxyphenylpropanoylspermine is reported and the locust muscle biological assay is described. Using this pharmacological screen, structure-activity relationships have been determined in our laboratories. These are reviewed in the light of the current literature. Voltage clamp studies of the synthetic analogue philanthotoxin-343 and the effects of this polyamine amide on glutamate receptors expressed in Xenopus oocytes are outlined. In conclusion, a description of our current ideas and understanding of the many sites and modes of action of the polyamine amides, based both upon our own studies and also upon those recently reported, is presented.
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, University of Nottingham, U.K.
authors.forename: I S
authors.initials: IS
authors.lastname: Blagbrough
authors.forename: P T
authors.initials: PT
authors.lastname: Brackley
authors.forename: M
authors.initials: M
authors.lastname: Bruce
authors.forename: B W
authors.initials: BW
authors.lastname: Bycroft
authors.forename: A J
authors.initials: AJ
authors.lastname: Mather
authors.forename: S
authors.initials: S
authors.lastname: Millington
authors.forename: H L
authors.initials: HL
authors.lastname: Sudan
authors.forename: P N
authors.initials: PN
authors.lastname: Usherwood
mesh_terms: D000818:Animals; D001681:Biological Assay; D005971:Glutamates; D006110:Grasshoppers; D007210:Indoleacetic Acids; D007306:Insecticides / Q000138:chemical synthesis / Q000737:chemistry*; D009132:Muscles / Q000187:drug effects / Q000378:metabolism; D009865:Oocytes / Q000378:metabolism; D010636:Phenols / Q000737:chemistry / Q000494:pharmacology; D010648:Phenylacetates / Q000737:chemistry / Q000494:pharmacology; D011073:Polyamines / Q000737:chemistry / Q000494:pharmacology; D017470:Receptors, Glutamate; D017981:Receptors, Neurotransmitter / Q000037:antagonists & inhibitors*; D013111:Spider Venoms / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014862:Wasp Venoms / Q000737:chemistry* / Q000494:pharmacology; D014982:Xenopus laevis
chemical_list: D005971:Glutamates; D007210:Indoleacetic Acids; D007306:Insecticides; D010636:Phenols; D010648:Phenylacetates; D011073:Polyamines; D017470:Receptors, Glutamate; D017981:Receptors, Neurotransmitter; D013111:Spider Venoms; D014862:Wasp Venoms; C558368:argiotoxin-636; C074003:philanthotoxin 343; C034092:delta-philanthotoxin