Polyamine toxins

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

Overstimulation of mammalian CNS receptors after cerebral ischaemia and trauma can result in irreversible brain damage. Certain polyamine toxins from... 

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 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]. 

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. 

As described for many polyamine toxins, the polyamine moiety is coupled via an amide bond to an aromatic moiety, which mostly consist of 2,4-dihydroxyphenylacetyl or indol-3-acetyl moieties. Nakanishi and coworkers as well as Blagbrough and colleagues conducted structure and function studies of polyamine toxin analogs to improve their potential as inhibitors of the nicotinic acetylchoHne receptor (for review see [21]). To date, many groups have focused on the development of novel polyamine toxin analogs as therapeutically active agents. Most of the syntheses in this field are already performed on soHd phase and will be discussed in Sect. 3. Some of the analogs (27-35) are depicted in Fig. 6. 

Fig. 6 Some examples of polyamine toxin analogs. They are divided into different sub- groups such as the analogs with bulky headgroups or analog-conjugates...

This preloaded resin has been [179] employed for the synthesis of [193] a polyamine toxin library... 

An example that starts the synthesis of polyamine toxins from a central amino group is shown in Scheme 13 [229,230]. The backbone is elongated by alternate coupling of benzyl-protected amines and bromides. Due to the protection group strategy consisting of orthogonal Boc- (128), benzyl- (138), and phthalimides (137) it is possible to synthesize polyamines from center to tail. Unfortunately, after three alkylation steps the overall yield is only 30%, which drops the overall yield to 10-30%. 

After pubfishing a mixed solution-solid phase synthesis of polyamine toxin HO-416b (274) in 1999 [257], Fukuyama et al. demonstrated the versatility of the Ns-strategy for the complete synthesis of longer polyamines on solid phase by the synthesis of PhTX-343 (27) [24,257] (Scheme 20). The... 

Keywords Ionotropic glutamate receptors Natural products Nicotinic acetylcholine receptors Polyamine toxin Solid-phase synthesis Spider and wasp... 

Another group of polyamine toxins isolated from funnel web spiders were isolated and characterized (compounds 11-14 Fig. 17.1) in a similar manner. These toxins are also named according to the molecular mass, such as the a-agatoxin with a molecular mass of 489 Da, named AG489 or Agel-489 (Skinner et al. 1989 ... 

Philanthotoxin-433 (16, PhTX-433 Fig. 17.1) is a structurally related, albeit somewhat simpler polyamine toxin, which was isolated from the Egyptian digger wasp Philanthus triangulum. It was isolated, characterized, and synthesized by a collaborative effort by Nakanishi, Usherwood, and coworkers (Eldefrawi et al. 1988). 

Among all the polyamine toxins, PhTX-433 has been most extensively used as template for stracture-activity relationship (SAR) studies, pioneered by the work of Nakanishi and coworkers, as described later (Strpmgaard et al. 2005 Andersen et al. 2006 Olsen et al. 2011). More recently, the structure of PhTX-433 and spider polyamine toxin NPTX-622B (17 Fig. 17.1) was combined in a spider-wasp hybrid analogue (18 Fig. 17.1) (Olsen et al. 2007). 

Polyamine toxins are so-called noncompetitive open ion channel blockers of the iGlu receptors (Strpmgaard and Mellor 2004 Mellor and Usherwood 2004 Strpmgaard et al. 2005), where they are believed to bind to the central ion channel... 

Chemical Synthesis of Spider and Wasp Polyamine Toxins... 

Polyamine toxins have been used as pharmacological tools for neurobiological studies, particular those related to iGlu receptors (Jackson and Usherwood 1988 Jackson and Parks 1989 Kawai et al. 1991). Early studies revealed that polyamine... 

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