Activity coefficients 1 -octanol-water partition coefficient correlations

Second, P-gp differs from other transporters in that it recognizes its substrates when dissolved in the lipid membrane [52], and not when dissolved in aqueous solution. The site of recognition and binding has been shown to be located in the membrane leaflet facing the cytosol [53, 54], This implies that the membrane concentration of the substrate, Csm, determines activation [57]. Since the nature of a molecular interaction is strongly influenced by the solvent, the lipid membrane must be taken into account as the solvent for the SAR analysis of P-gp. Under certain conditions, the effect of additional solvents or excipients (used to apply hydrophobic substrates or inhibitors) on the lipid membrane and/or on the transporter must also be considered. Lipophilicity of substrates has long been known to play an important role in P-gp-substrate interactions nevertheless, the correlation of the octanol/water partition coefficients with the concentration of half-maximum... 

The octanol-water partition coefficient Kow is widely used as a descriptor of hydrophobicity. Variation in /fow is primarily attributable to variation in activity coefficient in the aqueous phase (Miller et al. 1985) thus, the same correlations used for solubility in water are applicable to /fow. Most widely used is the Hansch-Leo compilation of data (Leo et al. 1971, Hansch and Leo 1979) and related predictive methods. Examples of Kow correlations are ... 

Partitioning into the CNS will be important for hallucinogens, as for any drug that acts centrally. Correlation between 1-octanol/water partition coefficients and human activity has been reported (13). Regression analysis of log human activity on log P yielded a parabolic fit with an optimum at log P 3.14. The derived equation accounted for only 62% of the variance but included compounds with a variety of substitution patterns and, presumably, qualitative differences in activity. 

Barfknecht, C. F., Nichols, D. E., and Dunn, W. J., Ill (1975) Correlation of psychotomimetic activity of phenethylamines and amphetamines with l-octanol/water partition coefficients. J. Med. Chem., 18 208-210. 

The octanol-water partition coefficient appears to correlate better with biological activity than partition coefficients in other solvent-water mixtures as, for example, hexane water, because the amphiphilic nature of octanol can accommodate a greater variety of more or less hydrophobic molecules. 

Litman etal. [ 391 analyzed a set of 34 diverse drugs and their effect on the kinetics of the ATPase activity of the microsomal membrane fraction of a P-gp overexpressing CHO cell line. They found a correlation (r=0.75) between the affinity of the modulators and their van der Waals surface area, while the affinity data did not correlate with the lipophilicity of the compounds, expressed as calculated octanol/ water partition coefficients. 

In view of the predictive properties of the octanol-water partition coefficient, logP, in the description of enzymatic activity [79], this parameter has received much attention. However, as argued in an early but still authoritative review compiled by Carrea and coworkers [80], its usefulness in the correlation of solvent effects on enantioselectivity appears to be limited. The problem is exemplified by the entries in Figure... 

Drug binding is enhanced by hydrophobicity in that portion of the drug that binds to the pocket toe. Quantitative structure-activity relationship (QSAR) analysis of these compounds have consistently shown that the most predictive parameter of antiviral activity is a measure of hydrophobicity, the octanol water partition coefficient (logP) [80,82,85]. These studies have also consistently shown that there is no apparent correlation between electrostatic potential or dipole moment and potency. 

The physicochemical properties that correlate with the biological property are likely to be related to the mechanism by which the chemicals cause the biological activity, and are often referred to as descriptors of the biological activity. Examples of physicochemical properties that often correlate with biological activity and used in the quantification of SARs include octanol-water partition coefficient (logP0/w), dissociation constant (p/<,), and molar refractivity (MR), among others. 

This area is a development in the usage of NDDO models that emphasizes their utility for large-scale problems. Structure-activity relationships (SARs) are widely used in the pharmaceutical industry to understand how the various features of biologically active molecules contribute to their activity. SARs typically take the form of equations, often linear equations, that quantify activity as a function of variables associated with the molecules. The molecular variables could include, for instance, molecular weight, dipole moment, hydrophobic surface area, octanol-water partition coefficient, vapor pressure, various descriptors associated with molecular geometry, etc. For example, Cramer, Famini, and Lowrey (1993) found a strong correlation (r = 0.958) between various computed properties for 44 alkylammonium ions and their ability to act as acetylcholinesterase inhibitors according to the equation... 

Attempts have been made to correlate the influence of solvents on enzyme activity, stability, and selectivity with physicochemical solvent characteristics such as relative permittivity, dipole moment, water miscibility, and hydrophobicity, as well as empirieal parameters of solvent polarity. However, no rationale of general validity has been found, except the simple rule that nonpolar hydrophobic solvents are generally better than polar hydrophilic ones. The best correlations are often obtained with the logarithm of the 1-octanol/water partition coefficient, Ig Pq/wj a quantitative measure of the solvent s hydrophobicity cf. Section 7.2). 

Barfknecht, C.F. Nichols, D.E., Dunn, W.J., III. Correlation of Psychotomimetic Activity of Phenethylamines and Amphetamines with 1-Octanol-water Partition Coefficients. J Med Chem, 18 208-210,1975. 

An empirical correlation (Lin and Sandler, 1999b) relates the octanol-water partition coefficient of solute z (which is the partitioning of the solute between water and water- saturated octanol) and the infinite dilution activity coefficients of the solute in water and in pure (not water saturated) octanol. 

Overviews of QSAR studies for aquatic toxicity of chemicals which show narcosis are extensively discussed in several publications [93,94]. At first sight, it is quite remarkable that QSAR equations for all kinds of different species are so similar. On the other hand, the explanation is rather simple. It is generally accepted that the mechanism of narcosis is not a very specific process and each compoimd has the same intrinsic activity. In other words the external concentration of a compound at a fixed effect (e.g. narcosis or death) is only a fimction of the probability of a compound to reach its site of action. For many chemicals for which bioaccumulation is not influenced by biotransformation reactions, this probability is correlated to the octanol-water partition coefficient (K ) and this explains directly the correlation between and the external effect concentrations. 

Numerous relationships exist among the structural characteristics, physicochemical properties, and/or biological qualities of classes of related compounds. Simple examples include bivariate correlations between physicochemical properties such as aqueous solubility and octanol-water partition coefficients (Jtow) and correlations between equilibrium constants of related sets of compounds. Perhaps the best-known attribute relationships to chemists are the correlations between reaction rate constants and equilibrium constants for related reactions commonly known as linear free-energy relationships or LFERs. The LFER concept also leads to the broader concepts of property-activity and structure-activity relationships (PARs and SARs), which seek to predict the environmental fate of related compounds or their bioactivity (bioaccumulation, biodegradation, toxicity) based on correlations with physicochemical properties or structural features of the compounds. Table 1 summarizes the types of attribute relationships that have been used in chemical fate studies and defines some important terms used in these relationships. 

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