Polyamine spider toxins

Usherwood, P.N. R. and Blagbrough, I. S. (1991). Spider toxins affecting glutamate receptors polyamines in therapeutical neurochemistry. Pharmacological Therapeutics 52 245-268. 

A number of invertebrate polyamine toxins have recently been shown to be open channel blockers of glutamate receptors initially at the neuromuscular junction of locusts [54] and recently on central mammalian neurones [54-57], These toxins include argiotoxin 636, Joro spider toxin and philanthotoxin. Although these polyamine toxins block NMDA receptors at least in some preparations, in others they also block responses mediated by AMPA receptors more selectively [58-60]. 

The Fukuyama amine synthesis has seen wide application in the context of natural product synthesis. Complex polyamine natural products that highlight the orthogonal nature of the nosyl protecting group, such as lipogrammistin-A12 and various spider toxins,13 have been efficiently synthesized. This protocol has also been used in the context of medicinal chemistry,14 glucosylamines,15 and blasticidin amino acids.16... 

Reactive functional groups withstand reactions with LR if proper conditions are chosen. The thionation of 7V (< -haloalkyl) amides with 0.5 equiv of LR yields the corresponding thioamides without attack at the halo substituent. Optically pure cj-thio-amides of Fmoc-asparagic and -glutamic acid (68) have heen prepared with another LR analog, 0,0-bis(tert-hutyldimethylsilyl)-4-methoxyhenzenephosphonothioate [p-MeO-C6H4-P(S)(OTB DMS)2]. The protected polyamine thioamide (69) is related to the spider toxin FTX. ... 

Some of the properties that would be required of a polyamine amide insecticide are an ability to gain entry into pest insects, resistance to metabolic degradation within these insects, and high potency at its site of action. There are, of course, other equally important considerations, such as persistence in the environment, cost of production, toxicity to man and other non-pest animals, and the impact on the ecosystem of the use of analogues of wasp and spider toxins as insecticides. 

The continuing interest in the polyamine amides as lead structures comes at a time of major changes in the insecticide industry, not least of which is a reappraisal of the so-called rational approach towards insecticide discovery. This may slow industrial research on these compounds. Also, developments involving natural products as starting points are being examined very critically by environmentalists and the polyamine amide toxins have not escap their attention. It has been suggested that the use of polyamine amide insecticides could lead to resistance to the natural products present in the venoms of spider and wasp. However, the potential consequences of this for the ecosystem in general are difficult to identify, let alone to estimate. 

Jackson H, Usherwood PN (1988) Spider toxins as tools for dissecting elements of excitatory amino add transmission. Trends Neurosci 11 278-283 Jasys VJ, Kelbaugh PR, Nason DM, PhiUips D, Rosnack KJ, Saccomano NA, Stroh JG, VoUonann RA (1990) Isolation, structure elucidation, and synthesis of novel hydroxylamine-containing polyamines from the venom of the Agelenopsis aperta spider. J Am Chem Soc 112 6696-6704... 

MeUor IR, Brier TJ, Pluteanu F, Str0mgaaid K, Saghyan A, Eldursi N, Brierley MJ, Andersen K, Jaroszewski JW, Krogsgaard-Larsen P, Usherwood PNR (2003) Modification of the phUantho-toxin-343 polyamine moiety results in different structure-activity profiles at muscle nicotinic ACh, NMDA and AMPA receptors. Neuropharmacology 44 70 MueUer AL, Albensi BC, Ganong AH, Reynolds LS, Jackson H (1991) Arylamine spider toxins antagonize NMDA receptor-mediated synaptic transmission in rat hippocampal slices. Synapse 9 244-250... 

Saito M, Kawai N, Miwa A, Pan-Hou H, Yoshioka M (1985) Spider toxin (JSTX) blocks glutamate synapse in hippocampal pyramidal neurons. Brain Res 346 397-399 Schafer A, Benz H, Fiedler W, Guggisberg A, Bienz S, Hesse M (1994) Polyamine toxins from spiders and wasps. In Cordell GA, Brossi A (eds) The alkaloids chemistry and pharmacology,... 

Polyamine toxins from spiders and wasps. In The Alkaloids, vol. 45, eds. G. Cordell and A. Brossi, pp. 1-125. New York Academic Press. 

Calcium-channel blockers and activators - nonpeptide toxins. Some polyamine toxins isolated from spiders and dinoflagellates that block Ca -entry include ITX (funnel toxin) and maitotoxin. 

A. L. Mueller R. Roeloffs H. Jackson, Pharmacology of Polyamine Toxins from Spiders and Wasps. In Alkaloids (San Diego), G. A. Cordell, Ed. Academic Press San Diego, CA, London, 1995 Vol. 46, pp 63-94. 

---