The figure shows Norbormide as a New Probe for Living Cell Imaging ; Chemical structures of (A) Norbormide and (B) its fluorescent derivative NRB-AF12. (C) Live cell imaging of LX2 hepatic stellate cells fluorescently labeled with 500 ηM NRB-AF12 for 30 min. Magnification 40x; scale bar 20 μm. (D) LX2 cells stained with NRB-AF12 were fixed and imaged by confocal microscopy. Magnification 60x; scale bar 20 μm.
Norbormide (Raticate, Shoxin) is a toxic composite used as a rodenticide or an acute acting selective rat toxicant. It has numerous mechanisms of action, acting as a vaso-constrictor 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 was discovered during routine screening of a diversity of agents for pharmacological activity at McNeil Laboratories, Fort Washington, Pennsylvania, USA. Norbormide was synthesized in the exploration for a novel anti-rheumatic drug. It was deliberated as a uncertain value for that movtive and was further studied as an appetite suppressant originally in house mice(Mus musculus)and cats(Felis catus), with no toxic effects ,and then in rats. The alterations in impressionable were so striking, it was at first assumed that a mistake had been produced. Nevertheless, the uttermost vulnerability of rats was established when the experiments were reiterated. It was further studied again and presented to representatives attending the 149th National Meeting of the Chemistry Society in Detroit, Michigan in 1965 as a infrequent species-specific rodenticide and marketed as Raticate and Shoxin. Its use reduced in the 1970s as anticoagulant toxins became more prevalent. Taste loathing had restricted its efficiency, and field efficacy outcomes were commonly sub-standard . Prior to the introduction of anticoagulants all rodenticides were acute-acting toxicants. Rodenticide study progressed remarkably between the 1940s and 1990. Sodium fluoro-acetate (1080) was established in the 1940s, first group anticoagulant rodenticides in the 1950s and 1960s,and cholecalciferol and second generation anticoagulant rodenticides in the 1970s and 1980s, partially to overcome resistance to first group anticoagulants that transpired where there had been extended use of first group compounds. Anticoagulant rodenticides have been the foremost development for the control of rodents worldwide for both crop protection and conservation . The slow onset of action ensuing ingestion of anticoagulant baits helps confirm that even wary rodents will ingest sufficient toxic bait to cause death. Hence, it is not surprising that after the introduction of warfarin and the other anticoagulants, the importance of the non-anticoagulants was reduced, at least for commensal rodent control . This applied to Norbormide as well as the older poisons such as strychnine and arsenic, notwithstanding the remarkable species specificity of Norbormide. Succeeding the emergence of physiological resistance in some populations of rodents, even to second group rodenticides, the finding of remnant of the second-generation anticoagulants in wildlife and queries about the humaneness of second-generation anticoagulants attentiveness in non-anticoagulants, or at slightest less-persistent ‘low residue’ pesticides, has revitalized and study on a variety of acute acting toxicants including norbormide has progressed.
Rat poison vendor’s stall at a market in Linxia City , China
Norbormide provokes vasoconstriction (narrowing) of small arteries and vasodilation (widening) of large arteries in rats , which induces a rapid fall in blood pressure. Death possibly results from circulatory disorders and heart failure . As it is acute-acting it is likely to be more humane than most other rodenticides, because of the somewhat short time to death and duration of symptoms of poisoning when associated with anticoagulant rodenticides and cholecalciferol. As noted above, norbormide is highly toxic to members of the genus Rattus compared with other mammals or birds . Rats are 150-fold and 40-fold more sensitive to norbormide than house mice and guinea pigs (Cavia porcellus) respectively, while most other mammals and birds tested are >200-fold less sensitive . Two New Zealand research teams, one presently sponsored by the Department of Conservation Predator Free 2050 fund assisting Land care Research with Orillion (formerly ACP Ltd),and the second generation through investment by Invasive Pest Control Ltd. ,are looking at different ways of improving the effectiveness of norbormide and creating it in forms which are more pleasant . If either or both groups are effective, it will be a huge advance for targeted pest control with no non-target influence.
Derivative and Mechanism of Action
Research have been done in which was studied for derivative compounds of Norbormide that are more toxic. Addition or substitution of various groups never turned out to give considerably more toxic compounds. In most cases compounds were acquired, being considerably less toxic. An issue of using Norbormide as a rodenticide is bait shyness; this signifies that after the rat consumes a small bit of it, the rat becomes ailing and evades the toxin at that time; likewise the savor is presumed to be awful. Currently, researcher has been seeking for prodrugs of Norbormide that delivers the toxicant slowly and thus detain the toxic impacts. Pro-drugs have been found that seem to have these properties. Following researches need to be done for improvement before usage ultimately could be possible.
The mechanism for the vasoconstrictor effect is expected to be arbitrated by the modulation of calcium influx. This influx of calcium can leads to contraction in the myocytes. Perhaps the influx of calcium is interceded by the phospholipase C (PLC)-coupled receptors, in rat peripheral artery myocytes. Further all study has revealed that in respiratory, urinary and gastrointestinal smooth muscle there was not any contraction by Norbormide. The signs of Norbormide were very alike to the improved known Ca2+ entry blocker agents. Consequently, norbormide is not solely species specific but as well as tissue specific. Norbormide has a strong influence on the mitochondria in the cell. So, Norbormide transmit through the outer mitochondrial membrane (OMM) to the inner mitochondrial space. At this location or at the matrix it persuades 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.The convey of Norborimide derives from a Translocation protein (TSPO) also identified as peripheral benzodiazepine receptor. The Translocation protein (TSPO) is selective for the norbormide transport in rats. There are a few discrepancies 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 outcome, possibly for the diverse magnitude of transport among rat and other species.
Signaling Mechanisms for the Selective Vasoconstrictor Effect of Norbormide on the Rat Small Arteries
Poos, G.I., et al., Structure-activity studies with the selective rat toxicant norbormide. 1966: p. 537-540.
Rennison D, Bova S, Cavalli M, Ricchelli F, Zulian A, Hopkins B, Brimble MA (Apr 2007). “Synthesis and activity studies of analogues of the rat selective toxicant norbormide”. Bioorganic and Medicinal Chemistry. 15 (8): 2963–74. doi:10.1016/j.bmc.2007.02.012. PMID 17321141.
Zulian A, Petronilli V, Bova S, Dabbeni-Sala F, Cargnelli G, Cavalli M, Rennison D, Stäb J, Laita O, Lee DJ, Brimble MA, Hopkins B, Bernardi P, Ricchelli F (Jul 2007). “Assessing the molecular basis for rat-selective induction of the mitochondrial permeability transition by norbormide”. Biochimica et Biophysica Acta. 1767 (7): 980–982.
Bova, S., et al., Relaxant and Ca2+ channel blocking properties of norbormide on rat non-vascular smooth muscles. European Journal of Pharmacology, 2003. 470(185-191).
National Center for Biotechnology Information. PubChem Database. Norbormide, CID=13814, https://pubchem.ncbi.nlm.nih.gov/compound/Norbormide.