Norbormide

Last updated
Norbormide
Norbormide.png
Names
Preferred IUPAC name
5-(α-Hydroxy-α-2-pyridylbenzyl)-7-(α-2-pyridylbenzylidene)-5-norbornene-2,3-dicarboximide
Systematic IUPAC name
(10E)-8-[hydroxy(phenyl)pyridin-2-ylmethyl]-10-[phenyl(pyridin-2-yl)methylidene]-4-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione
Identifiers
3D model (JSmol)
ChemSpider
ECHA InfoCard 100.012.354 OOjs UI icon edit-ltr-progressive.svg
EC Number
  • 213-589-6
KEGG
PubChem CID
UNII
  • InChI=1S/C33H25N3O3/c37-31-28-22-19-23(33(39,21-13-5-2-6-14-21)25-16-8-10-18-35-25)29(30(28)32(38)36-31)27(22)26(20-11-3-1-4-12-20)24-15-7-9-17-34-24/h1-19,22,28-30,39H,(H,36,37,38)/b27-26+
    Key: DNTHHIVFNQZZRD-CYYJNZCTSA-N
  • OC(C1=CC2C3C(C1\C2=C(/C1=CC=CC=C1)C1=CC=CC=N1)C(=O)NC3=O)(C1=CC=CC=C1)C1=NC=CC=C1
Properties
C33H25N3O3
Molar mass 511.570
Hazards
Occupational safety and health (OHS/OSH):
Main hazards
Toxic
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

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, [1] 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. [2]

Contents

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. [3]

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. [4] 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. [5] 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. [6] [7] [8]

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. [9] 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. [10] 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. [1] The cis-endo-threo isomer has been found to be the isomer with the most potent vasoconstrictor properties. [11] In this structure there is a hydrogen bond between the hydroxyl group and the adjacent pyridine ring. [5] 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. [12]

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. [12] 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. [12]

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. [12]

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. [12] 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. [1]

Mechanism of action

The mechanism for the vasoconstrictor effect is predicted to be mediated by the modulation of calcium influx. This influx of calcium can leads to contraction in the myocytes. Probably the influx of calcium is mediated by the phospholipase C (PLC)-coupled receptors, in rat peripheral artery myocytes. [13] [14]

Other research of Sergio Bova et al. has shown that in respiratory, urinary and gastrointestinal smooth muscle there was no contraction by norbormide. The symptoms of norbormide were very similar to the better known Ca2+ entry blocker agents. Therefore, norbormide is not only species specific but in addition tissue specific. [15]

Norbormide has a strong effect on the mitochondria in the cell. Therefore, norbormide transfer through the outer mitochondrial membrane (OMM) to the inner mitochondrial space. At this location or at the matrix it induce the permeability transition pore (PTP). This PTP is an inner mitochondrial membrane (IMM) channel, whose opening leads to an increasing permeability for ions with an exclusion size of about 1500 Da. [16] The transport of norborimide comes from a translocation protein (TSPO) also known as peripheral benzodiazepine receptor. The TSPO is selective for the norbormide transport in rats. In figure 6.1 shows the crucial alignment of rat, mouse and guinea pig LPSO. There are a few differences in amino acids, but the position of 113 is very similar in between the species and other species like dogs, humans and chickens. Where the rat have at position 113 a methionine (M) others species have a leucine amino acid. This results probably for the different amount of transport between rat and other species. [16]

Metabolism

A compound's toxicological property has been linked to metabolic pathways, which often differ in various species. For that reason the correlation between toxicity and metabolism has been observed to obtain a clear insight into cellular metabolism, both in vitro and in vivo conditions. [17] [18] [19]

In vitro experiment

In vitro studies on liver preparations from rats and other rodents revealed that hydroxylation is the major process during the metabolism of NRB. Furthermore, the metabolites between the sexes of the rat seemed to deviate from one another. [5] First and foremost when NRB had been incubated with the liver S9 fraction, a few metabolic products were observed. The S9 fraction has been defined as "Supernatant fraction obtained from an organ (usually liver) homogenate by centrifuging at 9000 g for 20 minutes in a suitable medium; this fraction contains cytosol and microsomes." [20] The S9 fraction consists of two components: the microsomes component which incorporates cytochrome P450 isoforms (phase I metabolism) [21] and the cytosolic component which contains transferases (phase II metabolism). [22] A mixture of four active endo-isomers of NRB (U, V, W en Y) formed four major metabolites in rat liver S9 and cytosolic preparations after incubation. The isomers are separately not pure compounds, but research with pure V isomer and a mixture of U and V isomers pointed out that each isomer undergoes metabolism to be formed into a single product in rat. Mass spectrometry confirmed that all metabolites had a mass consistent with a hydroxylated metabolite of NRB. Because female rats are more sensitive to NRB than the male species, the level of metabolites are higher in females than in males. [5] The same metabolites were found in guinea pigs, although the levels of metabolism in these rodents are considerately lower compared to those in rats. In mice two metabolites were detected: one metabolite of the V isomer (V1) which was also found in the rat preparations and another, new metabolite of the V isomer (V2). (Figure 7.1) These data acknowledge the link between the susceptibility to NRB and the production of different types and different levels of metabolites.

In vivo experiment

After collecting blood from rats 10 and 30 minutes after oral administration, plasma and red blood cell fractions were analyzed in search for either parent compounds or hydroxylated metabolites. However, neither were found, which either means that the absorption did not take place or the compounds underwent a quick clearance from the body. Whole blood samples certainly showed traces of the parent compound and a metabolite (M3) with molecular mass of 226, in samples from both female and male rats. The level in which this metabolite occurred, appeared to be once again higher in the female rats than in the male species. M3 was not found in any other rat or mouse tissue. This suggests that M3 may be formed by gut microflora in rats. [23] After NRB had orally been administered, an examination of both rat and mouse liver revealed traces of the parent compound. Comparing the metabolite levels in both sexes and species, a significantly higher amount was discovered in the female rats than in the male rats or the mice. HPLC chromatograms liver preparations from female of and male rats, display the detection of four metabolites (U1, V1, M1, M2). (Figure 7.2) Mass spectrometry had been used to identify these and easily so, because the hydroxylated metabolites were +16 amu higher than NRB. These studies confirmed that the metabolites were identical to those found in the in vitro preparations. [5] [23] The metabolites were not found in mouse liver preparations. Moreover, neither NRB parent compound nor its metabolites were discovered in the heart after oral administration in rats as well as mice. This lack of detectable metabolites implies that NRB is able to induce a lethal effect at extremely low levels. [23]

Adverse effects & effects on animals

Adverse effects

The effects of norbormide are caused by the endo-isomers, but the exo-isomers R, T and X showed no contractile effects on the rat arterio smooth muscle. There was only a relaxing effect on the muscle. [5] In animal studies of Rozkowksi, he showed that the effects that are caused by NRB are irreversible. [24] Another study has shown that there were respiratory depressions after the cardiovascular effects in the rats which were treated with norbormide in vivo. [25]

Effects on animals

NRB is specifically toxic to rats, but it's relatively harmless to other rodents and mammals. In all animals tested and also in the rat aorta and extravascular smooth muscle tissue, NRB exhibits vasorelaxant properties in the arteries. [13] Another effect of NRB is stimulation of corticosterone and aldosterone production in both rat and mice adrenal gland by enhancing late steps of steroid-hormone synthesis. [14]

Toxicity

The unique toxicity of NRB has been determined by performing animal experiments by using several species of rodents. The toxic dose was orally administered. [26] In the table the defined LD50 data illustrate the compound's specific toxicity. Rats, particularly the female species, experience even after administration of a small amount of NRB the effects of the toxin. NRB is toxic to guinea pigs and mouse either, but to a lesser extent. There is no reliable information available about LD50 values in humans. Although NRB is a rodenticide, and especially toxic for brown rats, human beings could be exposed to NRB through inhalation and dermal contact.

Exposure Acute toxic levelOral LD50 (mg/kg)

Acute toxicity studies in rats

A lethal dose of NRB to rats causes behavioural changes which look a lot like the signs associated to cyanide toxicity. The first indications of the NRB toxicity present themselves about ten minutes after administration. At first the rats start showing signs of increased motor activity and incoordination. Subsequently, the rats' hind extremities weaken and become ashen. Their breathing begins to be laboured and within a short period of time the rats suffer from series of convulsive movements. The spasm is followed by death, which occurs within 30 minutes in albino laboratory rats and with two hours in wild animals. [24] After examining isolated rat hearts in Langendorff preparations, a frequent in vitro technique, NRB also turned out to cause severe species-selective toxic effects on rat heart. [24] 2-10 μg NRB had been injected into the coronary vessel which resulted in a reduction of blood flow, attended with decreased cardiac contraction and a decreased heart rate. The rat hearts started beating quite irregularly. These irreversible effects weren't marked in the heart muscle (myocardium) as perhaps expected, but straight in the coronary arteries. [24] Additionally, it was confirmed that rats which were subjected to NRB treatment suffered from hyperventilation followed by cardiovascular effects. [25] Recent studies present NRB's ability to activate the mitochondrial permeability transition pore (MPTP) in isolated rat preparations. Cell apoptosis and necrosis are (amongst other things) regulated by MPT pores. It is understandable that such an abnormity in the mitochondrial membranes bring about issues in the cellular metabolism of the poisoned animal. [8]

Toxicity studies in mammals and birds

The members of the genus Rattus are highly sensitive to NRB, but other animals experience no toxic effects. Upon closer examination a 1000 mg/kg dose of norbormide didn't bring forth any toxic signs when orally administered to cats, chickens, dogs, monkeys, mice, swine or birds. This has been confirmed in the table below. So it is safe to say that NRB is relatively harmless to nonrat species. [24]

Related Research Articles

<span class="mw-page-title-main">ADME</span> Acronym for process of disposition of pharmaceutical compounds

ADME is the four-letter abbreviation (acronym) for absorption, distribution, metabolism, and excretion, and is mainly used in fields such as pharmacokinetics and pharmacology. The four letter stands for descriptors quantifying how a given drug interacts within body over time. The term ADME was first introduced in the 1960s, and has become a standard term widely used in scientific literature, teaching, drug regulations, and clinical practice.

<span class="mw-page-title-main">Ibotenic acid</span> Chemical compound

Ibotenic acid or (S)-2-amino-2-(3-hydroxyisoxazol-5-yl)acetic acid, also referred to as ibotenate, is a chemical compound and psychoactive drug which occurs naturally in Amanita muscaria and related species of mushrooms typically found in the temperate and boreal regions of the northern hemisphere. It is a prodrug of muscimol, broken down by the liver to that much more stable compound. It is a conformationally-restricted analogue of the neurotransmitter glutamate, and due to its structural similarity to this neurotransmitter, acts as a non-selective glutamate receptor agonist. Because of this, ibotenic acid can be a powerful neurotoxin in high doses, and is employed as a "brain-lesioning agent" through cranial injections in scientific research. The neurotoxic effects appear to be dose-related and risks are unclear through consumption of ibotenic-acid containing fungi, although thought to be negligible in small doses.

<span class="mw-page-title-main">Aniracetam</span> Medication

Aniracetam, also known as N-anisoyl-2-pyrrolidinone, is a racetam which is sold in Europe as a prescription drug. It is not approved by the Food and Drug Administration for use in the United States as a prescription medication or dietary supplement. Despite the FDA's lack of approval, the drug is readily available over-the-counter in misbranded dietary supplements.

<span class="mw-page-title-main">Rodenticide</span> Chemical used to kill rodents

Rodenticides are chemicals made and sold for the purpose of killing rodents. While commonly referred to as "rat poison", rodenticides are also used to kill mice, woodchucks, chipmunks, porcupines, nutria, beavers, and voles. Despite the crucial roles that rodents play in nature, there are times when they need to be controlled.

A prodrug is a pharmacologically inactive medication or compound that, after intake, is metabolized into a pharmacologically active drug. Instead of administering a drug directly, a corresponding prodrug can be used to improve how the drug is absorbed, distributed, metabolized, and excreted (ADME).

Drug metabolism is the metabolic breakdown of drugs by living organisms, usually through specialized enzymatic systems. More generally, xenobiotic metabolism is the set of metabolic pathways that modify the chemical structure of xenobiotics, which are compounds foreign to an organism's normal biochemistry, such as any drug or poison. These pathways are a form of biotransformation present in all major groups of organisms and are considered to be of ancient origin. These reactions often act to detoxify poisonous compounds. The study of drug metabolism is called pharmacokinetics.

<span class="mw-page-title-main">Iproniazid</span> Antidepressant

Iproniazid is a non-selective, irreversible monoamine oxidase inhibitor (MAOI) of the hydrazine class. It is a xenobiotic that was originally designed to treat tuberculosis, but was later most prominently used as an antidepressant drug. However, it was withdrawn from the market because of its hepatotoxicity. The medical use of iproniazid was discontinued in most of the world in the 1960s, but remained in use in France until its discontinuation in 2015.

<span class="mw-page-title-main">Ethyl loflazepate</span> Chemical compound

Ethyl loflazepate is a drug which is a benzodiazepine derivative. It possesses anxiolytic, anticonvulsant, sedative and skeletal muscle relaxant properties. In animal studies it was found to have low toxicity, although in rats evidence of pulmonary phospholipidosis occurred with pulmonary foam cells developing with long-term use of very high doses. Its elimination half-life is 51–103 hours. Its mechanism of action is similar to other benzodiazepines. Ethyl loflazepate also produces an active metabolite which is stronger than the parent compound. Ethyl loflazepate was designed to be a prodrug for descarboxyloflazepate, its active metabolite. It is the active metabolite which is responsible for most of the pharmacological effects rather than ethyl loflazepate. The main metabolites of ethyl loflazepate are descarbethoxyloflazepate, loflazepate and 3-hydroxydescarbethoxyloflazepate. Accumulation of the active metabolites of ethyl loflazepate are not affected by those with kidney failure or impairment. The symptoms of an overdose of ethyl loflazepate include sleepiness, agitation and ataxia. Hypotonia may also occur in severe cases. These symptoms occur much more frequently and severely in children. Death from therapeutic maintenance doses of ethyl loflazepate taken for 2 – 3 weeks has been reported in 3 elderly patients. The cause of death was asphyxia due to benzodiazepine toxicity. High doses of the antidepressant fluvoxamine may potentiate the adverse effects of ethyl loflazepate.

<span class="mw-page-title-main">Hexobarbital</span> Chemical compound

Hexobarbital or hexobarbitone, sold both in acid and sodium salt forms as Citopan, Evipan, and Tobinal, is a barbiturate derivative having hypnotic and sedative effects. It was used in the 1940s and 1950s as an agent for inducing anesthesia for surgery, as well as a rapid-acting, short-lasting hypnotic for general use, and has a relatively fast onset of effects and short duration of action. Modern barbiturates have largely supplanted the use of hexobarbital as an anesthetic, as they allow for better control of the depth of anesthesia. Hexobarbital is still used in some scientific research.

<span class="mw-page-title-main">Mesocarb</span> Stimulant drug

Mesocarb is a drug that is currently being developed for Parkinson's disease.

<span class="mw-page-title-main">Desmetramadol</span> Opioid painkiller medication

Desmetramadol, also known as O-desmethyltramadol (O-DSMT), is an opioid analgesic and the main active metabolite of tramadol. Tramadol is demethylated by the liver enzyme CYP2D6 to desmetramadol in the same way as codeine, and so similarly to the variation in effects seen with codeine, individuals who have a less active form of CYP2D6 will tend to have reduced analgesic effects from tramadol. Because desmetramadol itself does not need to be metabolized to induce an analgesic effect, it can be used in individuals with low CYP2D6 activity unlike tramadol.

<span class="mw-page-title-main">Bornaprine</span> Chemical compound

Bornaprine is a synthetic anticholinergic medication that is primarily used to treat Parkinson's disease. Additionally, bornaprine has been used to treat other disorders, including hyperhidrosis.

<i>N</i>-Methylphenethylamine Chemical compound

N-Methylphenethylamine (NMPEA) is a naturally occurring trace amine neuromodulator in humans that is derived from the trace amine, phenethylamine (PEA). It has been detected in human urine and is produced by phenylethanolamine N-methyltransferase with phenethylamine as a substrate, which significantly increases PEA's effects. PEA breaks down into phenylacetaldehyde which is further broken down into phenylacetic acid by monoamine oxidase. When this is inhibited by monoamine oxidase inhibitors, it allows more of the PEA to be metabolized into nymphetamine (NMPEA) and not wasted on the weaker inactive metabolites.

<span class="mw-page-title-main">Oripavine</span> Chemical compound

Oripavine is an opioid and the major metabolite of thebaine. It is the parent compound from which a series of semi-synthetic opioids are derived, which includes the compounds etorphine and buprenorphine. Although its analgesic potency is comparable to morphine, it is not used clinically due to its severe toxicity and low therapeutic index. Due to its use in manufacture of strong opioids, oripavine is a controlled substance in some jurisdictions.

<span class="mw-page-title-main">Remacemide</span> Chemical compound

Remacemide is a drug which acts as a low-affinity NMDA antagonist with sodium channel blocking properties. It has been studied for the treatment of acute ischemic stroke, epilepsy, Huntington's disease, and Parkinson's disease.

<span class="mw-page-title-main">Chlorophacinone</span> Chemical compound

Chlorophacinone is a first-generation anticoagulant rodenticide. The mechanism of action results in internal bleeding due to non-functional clotting factors. It was used as a toxin to control rodent populations. 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 and is subject to strict reporting requirements by facilities which produce, store, or use it in significant quantities.

α-Naphthylthiourea Chemical compound

α-Naphthylthiourea (ANTU) is an organosulfur compound with the formula C10H7NHC(S)NH2. This a white, crystalline powder although commercial samples may be off-white. It is used as a rodenticide and as such is fairly toxic. Naphthylthiourea is available as 10% active baits in suitable protein- or carbohydrate-rich materials and as a 20% tracking powder.

<span class="mw-page-title-main">3α-Androstanediol</span> Chemical compound

3α-Androstanediol also known as 5α-androstane-3α,17β-diol and sometimes shortened in the literature to 3α-diol, is an endogenous steroid hormone and neurosteroid and a metabolite of androgens like dihydrotestosterone (DHT).

<span class="mw-page-title-main">Fluparoxan</span> Chemical compound

Fluparoxan is a potent α2-adrenergic receptor antagonist with excellent selectivity for this receptor over the α1-adrenergic receptor (2,630-fold), and is the only well-studied α2-adrenergic receptor antagonist in its structural family which does not antagonize any variant of the imidazoline receptor. It was shown to possess central α2-adrenoceptor antagonist activity after oral doses in man and was patented as an antidepressant by Glaxo in the early 1980s, but its development was discontinued when the compound failed to show a clear clinical advantage over existing therapies.

<span class="mw-page-title-main">Threohydrobupropion</span> Type of substituted amphetamine derivative

Threohydrobupropion is a substituted amphetamine derivative—specifically a β-hydroxyamphetamine—and a major active metabolite of the antidepressant drug bupropion (Wellbutrin). Bupropion is a norepinephrine–dopamine reuptake inhibitor and nicotinic acetylcholine receptor negative allosteric modulator, with its metabolites contributing substantially to its activities. Threohydrobupropion exists as two isomers, (1R,2R)-threohydrobupropion and (1S,2S)-threohydrobupropion. Other metabolites of bupropion include hydroxybupropion and erythrohydrobupropion.

References

  1. 1 2 3 Rennison D, Bova S, Cavalli M, Ricchelli F, Zulian A, Hopkins B, Brimble MA (April 2007). "Synthesis and activity studies of analogues of the rat selective toxicant norbormide". Bioorganic & Medicinal Chemistry. 15 (8): 2963–74. doi:10.1016/j.bmc.2007.02.012. PMID   17321141.
  2. ↑ Zulian A, Petronilli V, Bova S, Dabbeni-Sala F, Cargnelli G, Cavalli M, et al. (July 2007). "Assessing the molecular basis for rat-selective induction of the mitochondrial permeability transition by norbormide". Biochimica et Biophysica Acta (BBA) - Bioenergetics. 1767 (7): 980–8. doi: 10.1016/j.bbabio.2007.04.002 . hdl: 11577/3426374 . PMID   17509521.
  3. ↑ "40 C.F.R.: Appendix A to Part 355—The List of Extremely Hazardous Substances and Their Threshold Planning Quantities" (PDF) (July 1, 2008 ed.). Government Printing Office. Archived from the original (PDF) on February 25, 2012. Retrieved October 29, 2011.
  4. ↑ Telle HJ (1967). "Some fields observations on the observations on the acceptability and effectiveness of norbormide to Rattus norvegicus". Who/VBC. 67 (39): 10.
  5. 1 2 3 4 5 6 Ravindran S, Hopkins B, Bova S, Rennison D, Brimble M, Tingle M (January 2009). "In vitro metabolism of norbormide in rat, mouse and guinea pig liver preparations". Environmental Toxicology and Pharmacology. 27 (1): 144–8. doi:10.1016/j.etap.2008.09.007. PMID   21783932.
  6. ↑ Bova S, Trevisi L, Cima L, Luciani S, Golovina V, Cargnelli G (February 2001). "Signaling mechanisms for the selective vasoconstrictor effect of norbormide on the rat small arteries". The Journal of Pharmacology and Experimental Therapeutics. 296 (2): 458–63. PMID   11160631.
  7. ↑ Cavalli M, Omiciuolo L, Cargnelli G, Cima L, Hopkins B, Bova S (September 2004). "Distribution of the vasoconstrictor and vasorelaxant effects of norbormide along the vascular tree of the rat". Life Sciences. 75 (18): 2157–65. doi:10.1016/j.lfs.2004.04.022. PMID   15325842.
  8. 1 2 Ricchelli F, Dabbeni-Sala F, Petronilli V, Bernardi P, Hopkins B, Bova S (June 2005). "Species-specific modulation of the mitochondrial permeability transition by norbormide". Biochimica et Biophysica Acta (BBA) - Bioenergetics. 1708 (2): 178–86. doi: 10.1016/j.bbabio.2005.03.002 . PMID   15953474.
  9. ↑ Nilsson, B., Stereochemistry of an Inactive Racemate of Norbormide - A Selective Rat Toxicant. Acta Chemica Scandinavica, 1968. 22(2). PMID   5700784
  10. ↑ Steel PJ, Brimble MA, Hopkins B, Rennison D (May 2004). "Two stereoisomers of the rat toxicant norbormide". Acta Crystallographica Section C. 60 (Pt 5): o374-6. doi:10.1107/S0108270104006845. hdl: 10092/365 . PMID   15131397.
  11. ↑ Brimble M.A. , e.a., 2004.
  12. 1 2 3 4 5 Poos GI, Mohrbacher RJ, Carson EL, Paragamian V, Puma BM, Rasmussen CR, Roszkowski AP (July 1966). "Structure-activity studies with the selective rat toxicant norbormide". Journal of Medicinal Chemistry. 9 (4): 537–40. doi:10.1021/jm00322a021. PMID   5968018.
  13. 1 2 Rennison D, Laita O, Bova S, Cavalli M, Hopkins B, Linthicum DS, Brimble MA (July 2012). "Design and synthesis of prodrugs of the rat selective toxicant norbormide". Bioorganic & Medicinal Chemistry. 20 (13): 3997–4011. doi:10.1016/j.bmc.2012.05.014. PMID   22658693.
  14. 1 2 Neri G, Tortorella C, Andreis PG, Bova S, Malendowicz LK, Ziolkowska A, Nussdorfer GG (March 2003). "Norbormide enhances late steps of steroid-hormone synthesis in rat and mouse adrenal cortex". The Journal of Steroid Biochemistry and Molecular Biology. 84 (4): 479–83. doi:10.1016/s0960-0760(03)00060-8. PMID   12732293. S2CID   10840313.
  15. ↑ Bova S, Cavalli M, Cima L, Luciani S, Saponara S, Sgaragli G, Cargnelli G, Fusi F (June 2003). "Relaxant and Ca2+ channel blocking properties of norbormide on rat non-vascular smooth muscles". European Journal of Pharmacology. 470 (3): 185–91. doi:10.1016/s0014-2999(03)01797-7. PMID   12798957.
  16. 1 2 Zulian A, Sileikytė J, Petronilli V, Bova S, Dabbeni-Sala F, Cargnelli G, Rennison D, Brimble MA, Hopkins B, Bernardi P, Ricchelli F (December 2011). "The translocator protein (peripheral benzodiazepine receptor) mediates rat-selective activation of the mitochondrial permeability transition by norbormide". Biochimica et Biophysica Acta (BBA) - Bioenergetics. 1807 (12): 1600–5. doi: 10.1016/j.bbabio.2011.08.007 . PMID   21889488.
  17. ↑ Mitchell JR, Jollow DJ, Potter WZ, Davis DC, Gillette JR, Brodie BB (October 1973). "Acetaminophen-induced hepatic necrosis. I. Role of drug metabolism". The Journal of Pharmacology and Experimental Therapeutics. 187 (1): 185–94. PMID   4746326.
  18. ↑ Henderson RF (December 1996). "Species differences in the metabolism of benzene". Environmental Health Perspectives. 104 Suppl 6: 1173–5. doi:10.1289/ehp.961041173. PMC   1469720 . PMID   9118889.
  19. ↑ Tingle MD, Mahmud R, Maggs JL, Pirmohamed M, Park BK (November 1997). "Comparison of the metabolism and toxicity of dapsone in rat, mouse and man". The Journal of Pharmacology and Experimental Therapeutics. 283 (2): 817–23. PMID   9353403.
  20. ↑ Duffus JH, Nordberg M, Templeton DM (January 2007). "Glossary of Terms Used in Toxicology, 2nd Edition". Pure and Applied Chemistry. 79 (7): 1153–344. doi: 10.1351/pac200779071153 . S2CID   98296965.
  21. ↑ Greim H, Snyder R (2008). Toxicology and risk assessment: a comprehensive introduction. Wiley-Interscience. p. 387.
  22. ↑ Vogel GH (2006). Drug discovery and evaluation: safety and pharmacokinetic assays. Springer. p. 509.
  23. 1 2 3 Ravindran S, Hopkins B, Bova S, Tingle M (July 2009). "In vivo metabolism of norbormide in rats and mice". Environmental Toxicology and Pharmacology. 28 (1): 147–51. doi:10.1016/j.etap.2009.03.013. PMID   21783995.
  24. 1 2 3 4 5 Roszkowski AP (August 1965). "The pharmacological properties of norbormide, a selective rat toxicant". The Journal of Pharmacology and Experimental Therapeutics. 149 (2): 288–99. PMID   4953462.
  25. 1 2 Yelnosky J, Lawlor R (September 1971). "Cardiovascular effects of norbormide". European Journal of Pharmacology. 16 (1): 117–9. doi:10.1016/0014-2999(71)90065-3. PMID   5157526.
  26. ↑ Russel RU. "Norbormide - a Rattus-specific toxic agent". J. Forensic Sci. 1965: 80–83.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.