Structure-potency expression

An alternative viewpoint for structure-activity investigations is to utilize quantitative models as probes into the mechanism of action of the set of compounds being studied. In this case it is most useful if the molecular descriptors are explicitly meaningful in terms of chemical reactivity or physiological behavior, e.g., distribution of the compound in an organism (see Table II). In a previous symposium, (18), we described our application of this approach toward the development of a quantitative structure-potency expression, equation 1,... 

The thiazides are the most widely used of the diuretic drugs. They are sulfonamide derivatives and are related in structure to the carbonic anhydrase inhibitors. The thiazides have significantly greater diuretic activity than acetazolamide, and they act on the kidney by different mechanisms. All thiazides affect the distal tubule, and all have equal maximum diuretic effect, differing only in potency, expressed on a per -milligram basis. 

This approach is not restricted to bacterial or viral cells. Mammalian cells under highly proliferating conditions can be cultured at increasing exposure to a compound in attempts to create resistant mutants. Alternatively, one can sometimes use a structural biology approach to predict amino acid changes that would abrogate inhibitor affinity from study of enzyme-inhibitor complex crystal structures. If the recombinant mutant enzyme displays the diminished inhibitor potency expected, one can then devise ways of expressing the mutant enzyme in a cell type of interest and look to see if the cellular phenotype is likewise abolished by the mutation. 

The mechanism of action of inhalational anesthetics is unknown. The diversity of chemical structures (inert gas xenon hydrocarbons halogenated hydrocarbons) possessing anesthetic activity appears to rule out involvement of specific receptors. According to one hypothesis, uptake into the hydrophobic interior of the plasmalemma of neurons results in inhibition of electrical excitability and impulse propagation in the brain. This concept would explain the correlation between anesthetic potency and lipophilicity of anesthetic drugs (A). However, an interaction with lipophilic domains of membrane proteins is also conceivable. Anesthetic potency can be expressed in terms of the minimal alveolar concentration (MAC) at which 50% of patients remain immobile following a defined painful stimulus (skin incision). Whereas the poorly lipophilic N2O must be inhaled in high concentrations (>70% of inspired air has to be replaced), much smaller concentrations (<5%) are required in the case of the more lipophilic halothane. 

Phannaceutical products must demonstrate and maintain established public standards for attributes that relate to their safety or effectiveness. In the United States these attributes are expressed as identity (e.g., chemical structure), strength (e.g., assay, content uniformity), quality (e.g., combination of certain physical, chemical, and biological attributes), purity (e.g., limits on impurities and degradation products), and potency (e.g., biological activity, bioavailability, bioequivalence) [10]. Public standards serve as one of several mechanisms for minimizing the risk of product-related injuries. In principle these standards should reflect the current state of scientific understanding and ensure and promote the development of high-quality products. 

However, in the first instance, QSAR attempts to express compound potency as a linear function of various structural and property descriptors D with coefficients weighting their relative importance ... 

The first chemical clue relating the structure of anesthetics to their potency was discovered in 1899 by a pharmacologist, Hans Horst Meyer, and an anesthetist, Charles Ernst Overton. Working independently, Meyer and Overton noted a strong correlation between the polarity of a compound and its potency as an anesthetic. They expressed polarity as the oil/gas partition coefficient, while anesthetic potency was expressed as the partial pressure in atmospheres. Figure 11.10 is a Meyer-Overton correlation for 18 anesthetics used on mice. Note that olive oil is used, and it has become the most commonly used reference solvent. 

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