Meyer-Overton relationships

Once a large database of anesthetic compounds is examined the correlation predicted by the Meyer-Overton relationship is less convincing. In Fig. 9, we show the... 

General anesthetics are soluble in lipids. Only a few are soluble in water. Furthermore, there is a well known correlation between anesthetic potency and lipid solubility. It is the Meyer-Overton rule that has been known for 80 years to researchers in anesthesia.. This relationship was thoroughly studied and reexamined in recent years (See ). In its most modem form the lipid solubility or oil/water partition coefTicient is plotted against the so-called righting reflex taken for a measure of anesthetic potency. It is log 1/p where p is the effective anesthetic pressure in atmospheres required to suppress the righting reflex of mice in half of the experimental animals On this relationship arc based the unitary hypothesis and the hydrophobic site theory which state that all general anesthetics act by the same mechanism at the same molecular or sub-cellular sites of the membrane and that the sites are hydrophobic. 

Ostwald solubility coefficient. The graph shows that an anaesthetic gas with a high oil solubility is effective at a low alveolar concentration and has a high potency. This relationship is the basis of the Meyer-Overton hypothesis of anaesthesia. 

The quantitative property-activity models, commonly referred to as those marking the beginning of systematic QSAR/QSPR studies [Richet, 1893], have come out from the search for relationships between the potency of local anesthetics and the oil/water partition coefficient [Meyer, 1899], between narcosis and chain length [Overton, 1901, 1991], and between narcosis and surface tension [Traube, 1904]. In particular, the concepts developed by Meyer and Overton are often referred to as the Meyer-Overton theory of narcotic action [Meyer, 1899 Overton, 1901]. 

The second objective is to apply our knowledge of interfacial systems to a concrete problem of considerable medical interest - the determination of a relationship between the interfacial behavior of anesthetics and their anesthetic activity. This represents an alternative view to the century-old Meyer-Overton hypothesis [14,15], which relates anesthetic activity of anesthetics to their solubility in the bulk oily phase. 

According to the Meyer-Overton hypothesis [14,15], the anesthetic potency of anesthetic compounds is proportional to their solubilities in a non-polar phase, similar to the interior of the neuronal membrane. The remarkable aceuracy of this relationship for all elinical and many other anesthetics led to its broader interpretation that anes-theties act inside the neuronal membrane [36]. Then, the Meyer-Overton hypothesis implies that the same concentration is required for all anesthetics to exert anesthetic action, irrespective of their molecular structure. Their action may be either nonspecific or directed at selected membrane receptors. 

In 1868 two Scottish scientists, Crum Brown and Fraser [4] recognized that a relation exists between the physiological action of a substance and its chemical composition and constitution. That recognition was in effect the birth of the science that has come to be known as quantitative structure-activity relationship (QSAR) studies a QSAR is a mathematical equation that relates a biological or other property to structural and/or physicochemical properties of a series of (usually) related compounds. Shortly afterwards, Richardson [5] showed that the narcotic effect of primary aliphatic alcohols varied with their molecular weight, and in 1893 Richet [6] observed that the toxicities of a variety of simple polar chemicals such as alcohols, ethers, and ketones were inversely correlated with their aqueous solubilities. Probably the best known of the very early work in the field was that of Overton [7] and Meyer [8], who found that the narcotic effect of simple chemicals increased with their oil-water partition coefficient and postulated that this reflected the partitioning of a chemical between the aqueous exobiophase and a lipophilic receptor. This, as it turned out, was most prescient, for about 70% of published QSARs contain a term relating to partition coefficient [9]. 

Despite the work of Overton and Meyer, it was to be many years before structure-activity relationships were explored further. In 1939 Ferguson [10] postulated that the toxic dose of a chemical is a constant fraction of its aqueous solubility hence toxicity should increase as aqueous solubility decreases. Because aqueous solubility and oil-water partition coefficient are inversely related, it follows that toxicity should increase with partition coefficient. Although this has been found to be true up to a point, it does not continue ad infinitum. Toxicity (and indeed, any biological response) generally increases initially with partition coefficient, but then tends to fall again. This can be explained simply as a reluctance of very hydrophobic chemicals to leave a lipid phase and enter the next aqueous biophase [11]. An example of this is shown by a QSAR that models toxicity of barbiturates to the mouse [12] ... 

Forty years later Meyer [1], and at the same time Overton [2], observed a linear relationship between the activity of narcotics and their oil-water partition coefficient. An 40 years after that, a thermodynamic interpretation of this relationship was provided by Ferguson [3], which also explained cut-off of biological activity that is sometimes observed after a certain lipophilicity range has been passed. 

It was at the turn of the twentieth century that the importance of lipid solubility in drug action was also independently described by Meyer and Overton (the significance of the oil/water partition coefficient was discussed in Chapter 2). The importance of lipid solubility in drug action subsequently became manifested in the lipoid theory of cellular depression. In essence, this theory correlated a pharmacological effect (e.g., CNS depression) with a physical property (i.e., lipid solubility) rather than a structure-activity relationship. In the process, the theory was attempting to explain the diverse chemical structures that exist within the hypnotic and general anesthetic classes of drugs (see Chapter 11). Today, we realize the limitations of the lipoid theory and appreciate that the distinction between physical and chemical factors is illusory, since chemical structure is a determinant of physical properties. 

More than a hundred years ago, Meyer and Overton made their seminal discovery on the correlation between oil/water partition coefficients and the narcotie potencies of small organic molecules (7,8). Ferguson extended this analysis by placing the relationship between depressant action and hydrophobicity in a thermodynamic context the relative saturation of the depressant in the biophase was a critical determinant of its narcotic potency (9). At this time, the success of the Hammett equation began to permeate structure-activity studies and hydrophobicity as a determinant was relegated to the background. In a landmark study, Hansch and his colleagues de-... 

In view of the early observations of Meyer and Overton on the relationship of tadpole narcosis to hydrophobicity, and later the modern version of aquatic toxicity by Hansch and Dunn/ " it is not surprising that simple narcosis is the main component of base-line toxicity and can be delineated by a single parameter, log P with a slope close to unity. When a certain structural class of potential toxicants such as anilines or acrylates, fit to a line with the same slope as alkanes, but with a greater intercept, the excess toxicity of this structural feature can be expressed quantitatively. Alternatively, if the toxicity of a variety of structures is plotted against log P, those appearing above the background line clearly exhibit this excess toxicity. 

The discovery of a parameter (olive oil/water partition coefficient) upon which a mechanistic interpretation for narcosis could be based was made independently six years later by Charles Ernest Overton at the University of Zurich (30-31) and by Hans Horst Meyer (32) and his collaborator Fritz Baum (33) at the University of Marburg. Prior to this discovery, Walter Dunzelt, a student of Meyer, attempted to confirm the Houdaille data on the relationship between water solubility and minimum toxic concentration, using tadpoles and small fish (34). 

Perhaps the most famous examples of early QSAR are seen in the linear relationships between the narcotic action of organic compounds and their oil/water partition coefficients (Meyer 1899 Overton 1899). Table 1.3 lists the anaesthetic activity of a series of alcohols along with a parameter, which describes their partition properties (see Box 1.2 in this chapter for a description of 7t). The relationship between this activity and the physicochemical descriptor can be expressed as a linear regression equation as shown below. 

Since the work of Meyer and Overton a century ago, lipophilicity has been recognized as a meaningful parameter in structure-activity relationship studies, and with the epoch-making contributions of Hansch, has become the single most informative and successful physicochemical property in medicinal... 

The history of quantitative structure-activity relationships dates back to the last century, when Crum-Brown and Fraser in 1865 postulated that there ought to be a relationship between physiological activities <1> and chemical structures C. Later, Richet correlated toxicities with aqueous solubility. Around 1900, Meyer and Overton found linear relationships between the narcotic potencies of organic compounds and their partitioning behavior. In the mid-1930s, Hammett defined a reaction constant p to describe the reactivity of aromatic systems R, expressed by rate constants k (or equilibrium constants K) and a parameter o to describe the electronic properties of aromatic substituents X (1 equation 1) (see Linear Free Energy Relationships (LFER)) ... 

Meanwhile attention was drawn to the overriding importance of a physical property when, at the turn of the present century, Overton and Meyer independently put forward a Lipoid Theory of Cellular Depression (Meyer, 1899 Overton, 1901). This stated that chemically inert substances, of widely different molecular structures, exert depressant properties on those cells (particularly those of the central nervous system) that are rich in lipids and that the higher the partition coefficient (between any lipid solvent and water) the greater the depressant action. This statement requires only insertion of the words, up to the point where hydrophilic properties are almost extinguished after partition coefficient to outline the present day viewpoint. It is now appreciated that the relationship between lipophilicity and depression of nerve functioning is a parabolic one, because substances that are entirely lipophilic become trapped in other lipids and do not enter the cell (Hansch et al., 1968). Table 2.1 offers... 

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