Uncoupling activity

A relationship correlating the weak acid uncouplers activity with their A %-, pAi°, and has been presented on the basis of protonophoric theory of uncoupling activity, in which the concentration of anionic ionophore (A ) within a biomembrane is supposed to be controlled by the ionic partition of A at the biomembrane solution interface according to Eq. (28) [19]. The biomembrane solution interface could be polarized or electrogenic [37]. Experimental results on the activities of uncouplers on rat liver mitochondria [30] have been explained reasonably [19,24]. 

Escher, B. I. Snozzi, M. Schwarzenbach, R. P, Uptake, speciation, and uncoupling activity of substituted phenols in energy transducing membranes, Environ. Sci. Technol. 30, 3071-3079 (1996). 

Krupka, R. M., Uncoupled active transport mechanisms accounting for low selectivity in multidrug carriers P-glycoprotein and SMR antiporters,... 

A kinetic model was developed to describe the pH-dependent uncoupling activity of substituted phenols in bacterial photosynthetic membranes [2]. In this model, the overall uncoupling activity is quantitatively separated into the contribution of membrane concentration, which can be estimated by the Kmw, and of intrinsic activity. The intrinsic activity of an uncoupler is influenced not only by the hydrophobicity and acidity, but also by steric effects and by the charge distribution within the molecule [2]. 

Miyoshi, H., Nishioka, T. and Fujita, T. (1987). Quantitative relationship between protonophoric and uncoupling activities of substituted phenols, Biochim. Biophys. Acta, 891, 194-204. 

The use of distribution coefficients for the QSAR treatment of ionizable compounds has been extended to consideration of ion-pair partitioning into biolipid phases. Two experimental methods for determining ion-pair partition coefficients are described. One is a single-phase titration in water-saturated octanol, in which case (for acids) log Pj = log P + pKa - pKa. The other is a two-phase titration (octanol/water) from which the ratio (P + 1)/(Pj + 1) can be calculated. An example outcome is that the uncoupling activity of phenols can be represented by an equation in log instead of log D and pKa. 

QSAR Using Log D and Log Pj. The uncoupling activity of the phenols from which Equation 8 was derived, was reanalyzed using log Dj (Table II). The activity highly correlates with the lipid concentration of the ion pair. Equation 14. This is satisfying in view of a proposed mechanism of uncoupling (17)... 

As shown in Equations 20 and 21, the uncoupling activity and antiinflammatory activity of fenamic acid analogs, including flufenamic and mefenamic acids, are very similar in their dependence on both hydro-phobic and electronic effects of substituents. In these equations, the subscript, i, means that the drug activities are calculated on the basis of concentration of the ionized form. It has been suggested that these two biological effects, which are also observed in many other acidic antiinflammatory drugs, have similar physicochemical mechanisms in the interaction with receptors (44). 

The uncoupling activity was measured with rat liver mitochondria with succinate as respiratory substrate (2). pl50 is defined as the negative log of the concentration of an uncoupler yielding half-maximal stimulation of oxygen uptake. We measured our pKa values in 50% ethanol, the log P s in the octanol/pH 7-buffer system and RM values on paraffin-oil-coated commercial thin-layer plates (Sil-G, Macherey u. Nagel, Diiren, Germany). 

Figure 7. Contribution of substituents in different positions of the molecule to uncoupling activity...

The remaining portion of this paper illustrates a useful approach to this kind of separation. Four activities of phenols will be examined, then uncoupling activity by a variety of agents and the bacteriostatic activity of carboxylic acids will be analyzed. 

Uncoupling Activity, Inhibition of Chloride Ion Transport and Physicocheiiiical... 

Burke JF, Whitehouse MW. 1967. Concerning the differences in uncoupling activity of isomeric dinitrophenols. Biochem Pharmacol 16 209-211. 

Whilst it seems possible that certain of the effects of anti-inflammatory compounds in vivo may be explained in terms of uncoupling activity (e.g. the increased oxygen consumption and hyperthermia in animals and man subjected to overdoses of acetylsalicylic acid), further work is needed to establish that lower doses of the drugs do, in fact, cause uncoupling, and that their anti-inflammatory activity is dependent on this. 

Terada H and Muraoka S, Physicochemical prqpertiesand uncoupling activity of 3 -substituted analogues of N-phenylanftiranilic acid. Mo/. Pharmacol., 8, 95-KB (1972). 

For the most part, with the compounds included in this study, maximum uncoupling activity (stimulation of state 4 respiration) was obtained for the oxidation of succinate and inhibition of malate state 3 respiration was most sensitive. Therefore, only data for state 4 stimulation for the oxidation of succinate and... 

Zychlinkski, L. and Zolnierowicz, S., Comparison of uncoupling activities of chlorophenoxy herbicides in rat liver mitochondria, Toxicol Lett, 52, 25-34, 1990. 

However, the majority of real systems cannot be quantified according to an unique elementary process. Generally, TSDC results are interpreted formally in terms of a distribution of parallel (uncoupled) activated Debye-like processes. Therefore, considering, as discussed in the first section, a distribution of activation times with a normalized probability function p(ln x), the polarization is given by ... 

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