As uncouplers of oxidation

Dinitrophenol (1 mM) and potassium cyanide (KCN) (5 mM) are used as uncouplers of oxidative phosphorylation from electron transport (105). 

Because rodent populations world-wide were becoming resistant to the widely used Warfarin-type anticoagulant poisons, a search was initiated to find a rodenticide with a different mode of action one that would be effective against these resistant rodents. This search led to the discovery of the toxic nature of a family of diphenyl amines which act as uncouplers of oxidative phosphorylation. A structure-activity relationship (SAR) study was undertaken to choose a derivative that would be both poisonous to rodents but still readily consumed by them. This approach led to the discovery of bromethalin,... 

Abo-Khatwa, A. N., Al-Robai, A. A., and Al-Jawhari, D. A., 1996. Lichen acids as uncouplers of oxidative phosphorylation of mouse-liver mitochondria. Nat. Toxins 4, 96-102. 

Hunt, D.A. and Tracy, M.F., Pyrrole insecticides A new class of agriculturally important insecticides functioning as uncouplers of oxidative phosphorylation, in Insecticides with novel modes of action, Ishaaya, I. and Degheele, D., Eds., Berlin Spriner-Verlag, 1998, p. 138. 

The inhibition of cyclooxygenase by NSAID occurs at concentrations (0.01-10 pg/ml) comparable to their therapeutic levels. On the contrary, much higher concentrations of these drugs are required to regulate other processes which might underly their anti-inflammatory effect, such as uncoupling of oxidative phosphorylation or inhibition of leukocyte phagocytosis. A remarkable parallelism has been... 

This experiment demonstrates that oxygen uptake in mitochondria is coupled to the synthesis of ATP, in that in the absence of ADP little oxygen uptake will occur even in the presence of excess respiratory substrate. This is called respiratory control. Certain compounds, of which 2,4-dinitrophenol is a well-known example, act as uncouplers of oxidative phosphorylation. On adding such a compound to mitochondria in the presence of substrate, a rapid rate of oxygen uptake is observed with no synthesis of ATP. 

Abo-Khatwa AN, Al-Robai AA, Al-Jawhari DA (1996) Lichen Acids as Uncoupler of Oxidative Phosphorylation of Mouse-liver Mitochondria. Natural Toxins 4 96... 

Sulflutamid or A/-ethylpetfluotoctanesulfonamide [4151 -50-2] CgF yS02NHC2H, is a slow-acting stomach poison used in baits for the control of ants and cockroaches. It acts as an uncoupler of oxidative phosphorylation. 

Many inhibitors of substrate oxidations, substrate transport, electron transport, and ATP synthesis are known including many well-known toxins (see Sherratt, 1981 Harold, 1986 Nicholls and Ferguson, 1992). These are not discussed here except to mention specific uncouplers of oxidative phosphorylation. Classic uncouplers such as 2,4-dinitrophenol have protonated and unprotonated forms, both of which are lipid soluble and cross the inner mitochondrial membrane discharging the proton gradient. This prevents ATP synthesis and stimulates respiration. 

Much information about the respiratory chain has been obtained by the use of inhibitors, and, conversely, this has provided knowledge about the mechanism of action of several poisons (Figure 12-7). They may be classified as inhibitors of the respiratory chain, inhibitors of oxidative phosphorylation, and uncouplers of oxidative phosphorylation. 

Carbonylcyanide-4-trilluoromethoxyphenylhydrazone is known as a protonophore or uncoupler of oxidative phosphorylation in bioelectrochemistry because it disrupts the tight coupling between electron transport and the ATP synthase. Uncouplers act by dis-... 

Metabolic acidosis follows, and an increased anion gap results from accumulation of lactate as well as excretion of bicarbonate by the kidney to compensate for respiratory alkalosis. Arterial blood gas testing often reveals this mixed respiratory alkalosis and metabolic acidosis. Body temperature may be elevated owing to uncoupling of oxidative phosphorylation. Severe hyperthermia may occur in serious cases. Vomiting and hyperpnea as well as hyperthermia contribute to fluid loss and dehydration. With very severe poisoning, profound metabolic acidosis, seizures, coma. 

Dinitrophenols had been used as insecticides since 1892 but it was not until the 1930s that their value as herbicides was discovered and 4,6-dinitro-o-cresol (DNOC) was introduced. The trouble with dinitrophenols was their toxicity to all living organisms that respire. Their mode of action is through the uncoupling of oxidative phosphorylation, an effect that leads to a rapid death of any organism that comes into contact with the chemical, including the operator. 

Acute toxicity to aquatic species can be rationalized mechanistically by one of two types of interactions nonspecific mechanisms (called narcosis) or specific mechanisms. The latter involves specific interactions, such as covalent electrophilic reactions with biological macromolecules, or specific noncovalent interactions that cause toxicity, such as uncoupling of phosphorylative oxidation, among others. Most chemicals that are toxic to aquatic organisms are narcotic. Some have both narcotic and specific mechanisms. A narcotic chemical enters the cellular membranes of the organism and, by its mere presence, causes perturbations in the membranes to the extent that alterations in the function of the membranes occur, resulting in toxicity. 

A few caveats are in order as to what defines a lead. Firstly, a lead is more than just a compound that shows a defined level of activity in a primary screen. The screen must have been validated usually this will be by obtaining the expected responses from pharmacological standards or known drugs. Any reasons for false positives must be understood. Certain substances such as chemically reactive or unstable compounds, protein denaturants, membrane destabilizing agents or uncouplers of oxidative phosphorylation will record as active in a great variety of screens. These must be recognized and eliminated by suitable secondary procedures. 

The uncoupling of oxidative phosphorylation stops ATP being produced by this process, and so the energy is dissipated as heat. The patient therefore suffers hyperpyrexia and sweating. Again, this produces dehydration. 

---