Uncouplers physicochemical properties

In this chapter, the voltammetric study of local anesthetics (procaine and related compounds) [14—16], antihistamines (doxylamine and related compounds) [17,22], and uncouplers (2,4-dinitrophenol and related compounds) [18] at nitrobenzene (NB]Uwater (W) and 1,2-dichloroethane (DCE)-water (W) interfaces is discussed. Potential step voltammetry (chronoamperometry) or normal pulse voltammetry (NPV) and potential sweep voltammetry or cyclic voltammetry (CV) have been employed. Theoretical equations of the half-wave potential vs. pH diagram are derived and applied to interpret the midpoint potential or half-wave potential vs. pH plots to evaluate physicochemical properties, including the partition coefficients and dissociation constants of the drugs. Voltammetric study of the kinetics of protonation of base (procaine) in aqueous solution is also discussed. Finally, application to structure-activity relationship and mode of action study will be discussed briefly. 

Terada H and Muraoka S, Physicochemical properties and uncoupling activity of 3 -substituted analogues of N-phenylanthranilic acid. Mol. Pharmacol, 8, 95-103 (1972). NB See separate entry no. 552. 

Detailed mathematical studies of the relationship between uncoupling potency and physicochemical properties have been published for several classes of uncoupler, including phenols [81-89], arylhydrazones [90, 91], salicylanilides [81, 92, 93], pyrroles [94], benzimidazoles [81], coumarins [95, 96] and diarylamines [97-99]. Although the details of these analyses differ, there are several physicochemical parameters that are common to all and therefore appear to be the key properties required for uncoupling. These are acid strength, lipophilidty, and often a measure of the steric bulk of substituents adjacent to the acidic centre [94]. 

It is not possible to formulate a simple set of rules that can accurately predict from physicochemical properties whether or not a compound will be an efficient uncoupler. However, some general guidelines for combinations of log P and pKa that can lead to uncoupling can be devised and these are illustrated in Fig. 13.4.6, with some selected examples marked [102]. Thus, the compound should be weakly acidic, with a between 4 and 8, and have a moderately high log P. Notably, the properties of the basic uncoupler AU-1421 (1) also fall within this range (log P 5.5, basic pK 7.4) [30]. 

Hydrazones prepared by the reaction of aryldiazonium salts with malononitrile (trivially named carbonyl cyanide phenylhydrazones, or CCPs) have been known as uncouplers for many years [114]. Studies on the relationship between physicochemical properties and uncoupling potency have been reported [90, 91], and these show that this relationship is very similar to those for other classes of weakly acidic protonophoric uncouplers. Thus, two of the most potent uncouplers of... 

---