Norbormide (Raticate, Shoxin) is a toxic compound used as a rodenticide. It has several mechanisms of action, acting as a vasoconstrictor and calcium channel blocker, but is selectively toxic to rats and has relatively low toxicity to other species, due to a species specific action of opening the permeability transition pores in rat mitochondria. It is classified as an extremely hazardous substance in the United States as defined in Section 302 of the U.S. Emergency Planning and Community Right-to-Know Act (42 U.S.C. 11002), and is subject to strict reporting requirements by facilities which produce, store, or use it in significant quantities.
History In the early 1960s norbormide was developed to serve as a non-anticoagulant rat poison. During the 1970s, however, the utilization of this rodenticide decreased, since anticoagulant toxins seemed to be more effective against a wider range of rodents. NRB only kills rodents of the genus Rattus (R. norvegicus, R. exulans and R. rattus) and happens to be moderately innocent to other rodents and mammals. Although many view its selective feature as a disadvantage, scientists of Landcare Research in New Zealand search for ways to improve this rodenticide and develop several analogues.
Structure and reactivity Norbormide is an organic compound with the following systematic name: 5-(α-hydroxy-α-2-pyridylbenzyl)-7-(α-2-pyridylbenzylidene)-5-norbornene-2,3-dicarboximide. The structure consists of a norbornene ring, that is merged with an imide ring opposite to the double bond. One of the carbon atoms of this double bond is connected to another carbon atom, that is bound to a hydroxyl, a pyridyl and a phenyl group. The bridging carbon of the norbornene ring is double bonded to a carbon atom to which a pyridyl and a phenyl group are attached. There are eight possible stereoisomers of norbormide. On the exocyclic double bond there is cis/trans-isomerism. The imide ring can have an endo or an exo orientation and for the hydroxyl group erythro and threo isomers are possible. The vasoconstrictor properties of norbormide turn out to be very dependent on stereochemistry. Only the endo isomers are toxic in rats and the threo isomers are ten times as potent as the erythro isomers. The cis-endo-threo isomer has been found to be the isomer with the most potent vasoconstrictor properties. In this structure there is a hydrogen bond between the hydroxyl group and the adjacent pyridine ring. Studies reveal that norbormide toxicity is sensitive to structural changes, in almost all cases the toxicity decreases due to structural changes. Only substitution of the NH proton of the imide with certain groups could give toxic activity comparable to norbormide itself.
Synthesis Since NRB causes bait shyness in rats and rats therefore often only take sub lethal doses, studies have been performed in search of NRB derivatives that are more toxic than NRB itself. In this case, substitutions have taken only place at the imide-group of NRB. The common structure for each of this derivatives is shown in figure 4.1, where R is a changeable group. At position R, different hydrocarbon groups were placed. None of them were more toxic than NRB, so a different strategy was tried. In a second study there has been looked at different ring analogues of NRB. None of these different ring analogues were proven more toxic than NRB. Another type of reaction that has been studied is the making of prodrugs. These prodrugs were synthesized in order to overcome bait shyness. The goal of the study was creating a prodrug that tasted better than NRB and was, once it had entered the body, metabolized to NRB. Three different starting structures were used, seen in figures 4.2;4.3 and 4.4. In figures 4.5 and 4.6 it is shown how the starting structures were synthesized out of NRB. Only compound 19 (figure 4.7) was promising, because it delayed to onset of symptoms and it is more palatable to rats (shown in figure 4.8), but there has to be some more research on this compound before it can be used.
Available forms
Different stereoisomers During the synthesis of norbormide, five of the eight possible stereoisomers are formed in a significant amount, namely all the endo stereoisomers and the cis-exo-stereoisomer. Most of the potency of norbormide is due to the trans-endo-threo (LD50 = 0.50 mg/kg (rat)) and the cis-endo-threo isomers (LD50 = 0.15 mg/kg (rat)). These two isomers form approximately half of the commercial mixture.
Derivatives Studies have been done in which was searched for derivative compounds of norbormide that are more toxic. Addition or substitution of miscellaneous groups never turned out to give considerably more toxic compounds. In most cases compounds were obtained, being significantly less toxic. A problem of using norbormide as a rodenticide is bait shyness, this means that after the rat eats a little bit of it, the rat gets ill and avoids the toxin then, also the taste is supposed to be bad. Recent studies have been looking for prodrugs of norbormide that release the toxicant slowly and thereby delay the toxic effects. Prodrugs have been found that appear to have these properties. Subsequent studies need to be done for refinement before usage eventually might be possible.
… excerpt ends here. Continue reading the full article.
