Meyer-Overton correlation

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. 

The slope of the regression line implies that the MAC (minimal alveolar concentration effective in 50 percent of animals) is inversely proportional to partition coefficient or potency is directly proportional to partition coefficient. The Meyer-Overton correlation suggests that the site at which anesthetics bind is primarily a hydrophobic environment. Although a wide variety of compounds lie on the Meyer-Overton correlation line, there are many compounds that do not. This suggests that the chemical properties of the anesthetic site differ from those of olive oil. 

Figure 11.10 Meyer-Overton correlation for volatile general anesthetics in mice. The slope of the regression line is -1.02 and the correlation coefficient, r2 = 0.997. CTF, carbon tetrafluoride NIT, nitrogen ARG, argon PFE, perfluoroethane SHF, sulfur hexafluoride KRY, krypton N02, nitrous oxide ETH, ethylene XEN, xenon DDM, dichlorodifluoromethane CYC, cyclopropane FLU, fluroxene DEE, diethylether ENF, enflurane ISO, isoflurane HAL, halothane CHL, chloroform MOF, methoxyflurane.

General anesthetics are usually small solutes with relatively simple molecular structure. As overviewed before, Meyer and Overton have proposed that the potency of general anesthetics correlates with their solubility in organic solvents (the Meyer-Overton theory) almost a century ago. On the other hand, local anesthetics widely used are positively charged amphiphiles in solution and reversibly block the nerve conduction. We expect that the partition of both general and local anesthetics into lipid bilayer membranes plays a key role in controlling the anesthetic potency. Bilayer interfaces are crucial for the delivery of the anesthetics. 

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. 

The correlation between anaesthetic potency and lipid solubility shown in Fig. 2.10 is valid for most inhaled anaesthetics and the product MAC X oil/gas partition coefficient (which should of course be a constant) varies by only a factor of 2 or 3 for potencies ranging over 100 000-fold. This constancy implies that inhaled anaesthetics act in the same manner at a specific hydrophobic site (the so-called unitary theory of anaesthesia). This has been challenged by more recent work that has identified compounds, including alkanes and poly-halogenated and perfluorinated compounds, which do not obey the Meyer- Overton hypothesis. It has been suggested that a contributory cause of deviation from this hypothesis may be the choice of lipid to represent the anaesthetic site of action of these compounds, implying that there may be multiple sites of action for inhaled anaesthetics. 

The search for physical chemical correlates of drug action began as early as 1899 with the Meyer-Overton theory which stated that the potency of an anesthetic was directly proportional to its oil. water partition coefficient. The more lipid soluble the compound was, the more readily it was thought to penetrate the central nervous system. 

In 1899 Overton (13) and Meyer (1 ) correlated narcotic activity with lipid solubility (chloroform-water partition coefficients) of a wide variety of non-ionized compounds. They found that narcotic activity increased with increasing lipophilicity until lipid solubility became so high that the substance was virtually water insoluble. They also found that these compounds penetrated tissue cells as though the membranes were lipid in nature. This is the first reported correlation between partition coefficients and biological activity. A second major development in QSAR occurred in 1939 when Ferguson (15) was able to calculate toxic concentrations of a series of compounds from solubility and vapor pressure data. 

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... 

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]. 

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. 

Based on the earlier work of Meyer and Overton, who showed that the narcotic effect of anesthetics was related to their oil/water partition coefficients, Hansch and his co-workers have demonstrated unequivocally the importance of hydrophobic parameters such as log P (where P is, usually, the octanol/water partition coefficient) in QSAR analysis.28 The so-called classical QSAR approach, pioneered by Hansch, involves stepwise multiple regression analysis (MRA) in the generation of activity correlations with structural descriptors, such as physicochemical parameters (log P, molar refractivity, etc.) or substituent constants such as ir, a, and Es (where these represent hydrophobic, electronic, and steric effects, respectively). The Hansch approach has been very successful in accurately predicting effects in many biological systems, some of which have been subsequently rationalized by inspection of the three-dimensional structures of receptor proteins.28 The use of log P (and its associated substituent parameter, tr) is very important in toxicity,29-32 as well as in other forms of bioactivity, because of the role of hydrophobicity in molecular transport across cell membranes and other biological barriers. 

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-... 

Early in this century, Meyer (109) and Overton (110) showed that the relative potencies of drugs that affect the nervous system correlated with their oil/water partition coefficients. Fifty years later it was shown that partition coefficients in different solvent systems were correlated (111), thus establishing the basis for an extrathermodynamical treatment of partition coefficients. 

The classic experiments were those performed by Ernest Overton and Hans Meyer at the turn of the twentieth century, where tadpoles were placed in solutions containing alcohols of increasing hydrophobicity. They found a correlation between the concentration of the alcohol required to cause cessation of movement and the concentration of the alcohol distributed into the lipid phase of a lipid-water mixture. The ratio of the concentration in the lipid phase to the concentration in the aqueous phase at equilibrium is known as the Overton-Meyer or lipid-water partition coefficient. The higher the partition coefficient, the less alcohol was needed to cause cessation of movement. 

Meyer and Overton further expanded their theory and suggested that the correlation may be established and observed between lipid solubility and the central nervous system (CNS) depressant aetivity profde. The CNS-depressant activity is foimd to be directly proportional to the partition coefficient of the drug substance . 

Overton and Meyer both used olive oil as a partitioning system to model the physicochemical properties of the putative membrane lipoid site of action. Although Overton attempted to use melted cholesterol and other substances he thought might serve as a better reference phase, he abandoned this approach due to problems with the formation of inseparable emulsions (31). Collander in Finland (65) experimented with a variety of aqueous organic solvent systems and found that for many simple nonelectrolytes, the values were well-correlated according to the following equation ... 

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