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| Names | |
|---|---|
| Preferred IUPAC name (6Z,8S,8aS)-8-Methyl-6-[(2R)-2-methylhexylidene]octahydroindolizin-8-ol | |
| Other names Pumiliotoxin 251D | |
| Identifiers | |
3D model (JSmol) | |
| ChEMBL | |
| ChemSpider |
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| KEGG | |
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| Properties | |
| C16H29NO | |
| Molar mass | 251.414 g·mol−1 |
| Hazards | |
| Occupational safety and health (OHS/OSH): | |
Main hazards | Toxic |
Except where otherwise noted, data are given for materials in theirstandard state (at 25 °C [77 °F], 100 kPa). | |
Pumiliotoxin 251D is a toxic organic compound. It is found in the skin ofpoison frogs from the generaDendrobates,Epipedobates,Minyobates, andPhyllobates[1][2] and toads from the genusMelanophryniscus.[3] Its name comes from thepumiliotoxin family (PTXs) and its molecular mass of 251 daltons. When the toxin enters the bloodstream through cuts in the skin or by ingestion,[4] it can causehyperactivity,convulsions,cardiac arrest and ultimately death. It is especially toxic toarthropods (e.g. mosquitoes), even at low (naturally occurring) concentrations.[5]
The chiral centers in pumiliotoxin 251D can give several stereoisomers of the compound. Only one form of the toxin is present in nature and has toxic properties.
_and_(-).jpg)
Twoenantiomers of pumiliotoxin 251D. On the left the plus enantiomer is shown which is toxic. On the right side the minus enantiomer, which is not toxic, is shown.
The side chain conformation of substituents at the C-2’ position plays an important role in the toxicity of the compound.[6]
The synthesis of pumiliotoxin 251D is quite complex and contains multiple steps. It can be achieved starting from the N-Boc derivative of L-proline methyl ester.
Pumiliotoxin (−)-251D can be synthesized in a similar way with minor alterations to the overall synthesis.[6]
In general, pumiliotoxins are known as positive modulators ofvoltage-gated sodium channels (VGSCs,membrane proteins). Pumiliotoxin 251D is not such a poison. However, it does block the influx of Na+ ions in mammalian VGSCs.
Pumiliotoxin 251D is able to shift the V1/2. This is the potential at which the sodium open probability is half maximal. Both the steady-state activation and inactivation curves of each mammalian VGSCs are shifted to a more negative potential.[1]
PTX 251D shifts the V1/2 of insect VGSCs even further than the mammalian VSGCs. This explains why it is especially toxic to insects, like mosquitoes. Furthermore, the presence of PTX 251D results in a six time higher permeability of the VGSCs for K+ ions. This severely disturbs the delicate sodium-potassium equilibrium in the nerve system.
The effect of pumiliotoxin 251D on thevoltage-gated potassium channels (VGPCs) currents is quite small. The toxic has an effect on the deactivation kinetics of the potassium channel. It inhibits its inactivation. This effect is still under investigation.[1]
PTX 251D also completely inhibits the activity of Ca2+-stimulatedATPase.[7] This results in a decreased reuptake of Ca2+ and thus a high concentration of free Ca2+ in the organism. This may be related to thepotentiation andprolongation ofmuscle twitch caused by the inhibition.[7]
The mechanism ofbiotransformation of PTX 251D is still unknown.
Pumiliotoxin is a toxin found in poison dart frogs (genus Dendrobates and Phyllobates). It affects the calcium channels, interfering with muscle contraction in the heart and skeletal muscle.
PTX 251D has several effects. It rapidly induces convulsions and death to mice and insects (LD50 being, respectively, 10 mg/kg and 150 ng/larvae).[1] These convulsions are the result of the uncontrollable distortion of the sodium-potassium equilibrium in theneurons. This is caused by the inhibition of the VGSCs.
It also acts as cardiac depressor, causing cardiac arrest. This can be explained by its negative effect on the cardiac VGSC hNav1.5/β1.[1]
Although nothing is known of how well PTX 251D penetrates into the brain where convulsions are originated, the observation of convulsions can be explained through inhibition of VGPCs.[1]
Symptomatic treatment of PTX 251D poisoning include reducing the convulsions usingcarbamazepine. This drug targets the affected VGSCs.Phenobarbital also shows positive effects by interacting with the affectedCa2+ channels. Ineffective drugs includediazepam anddizocilpine.[1]
