Narcosis potency

Discovery of the Correlation Between Narcosis Potency and Water Solubility and Molecular Weight... 

Discovery of the Correlation of Narcosis Potency and Partition Coefficient... 

For the next five decades, the correlation of partition coefficient with narcosis potency continued to be an important area for research, with studies of various compounds performed using whole organisms, organs, cells, and enzymes. This work has been discussed in a number of major reviews (42-51), and in papers from an international conference on this subject held in Paris in 1950 (52). 

The induction of unconsciousness may be the result of exposure to excessive concentrations of toxic solvents such as carbon tetrachloride or vinyl chloride, as occasionally occurs in industrial situations (solvent narcosis). Also, volatile and nonvolatile anesthetic drugs such as halothane and thiopental, respectively, cause the same physiological effect. The mechanism(s) underlying anesthesia is not fully understood, although various theories have been proposed. Many of these have centered on the correlation between certain physicochemical properties and anesthetic potency. Thus, the oil/water partition coefficient, the ability to reduce surface tension, and the ability to induce the formation of clathrate compounds with water are all correlated with anesthetic potency. It seems that each of these characteristics are all connected to hydrophobicity, and so the site of action may be a hydrophobic region in a membrane or protein. Thus, again, physicochemical properties determine biological activity. 

The quantitative property-activity models, commonly referred to as marking the beginning of QSAR/QSPR studies [Richet, 1893], have come 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 Overton, 1991], and between narcosis and surface tension (Traube, 1904). 

ANTIFUNGAL activity. It produces narcosis and convulsions in animals, also hypotension and respiratory depression. It has been used (in eastern Europe) as an antitussive with similar potency to codeine. 

Interest has existed for some time regarding what property of a molecule is responsible for the production of a specific type of biological response (18-20). In the case of narcosis or anesthetic response, this was complicated by the finding that narcosis could be produced by a wide variety of different, appairently unrelated compounds. Including simple saturated monohydric alcohols. Perhaps the earliest systematic investigation of the mechanistic basis of narcosis was that of Cros at the University of Strasbourg, who in 1863 reported that toxicity of simple alcohols administered to mammals increases with decreasing water solubility, up to a point of maximum potency, beyond which it decreases, until the alcohols become very insoluble and act like fatty substances... 

Dunzelt concluded in his 1896 Inaugural Dissertation (34) that although this correlation seemed to be generally correct, it did not hold for two compounds. Bromal hydrate was found to be very soluble in water and produce narcosis in fish at low concentrations. By contrast, methyl urethane was found to produce only a slight narcotic effect, even though it was only slightly soluble in water. This finding of Dunzelt may have provided Meyer with the impetus to search for another chemical property that better correlated with narcotic potency. Meyer further... 

It is possible to estimate, for some aquatic organisms, the whole-body toxicant concentration for some narcotic and narcotic-like organic chemicals (McCarty 1987). This was achieved by exploiting the interrelationship of a molecular descriptor (log octanol/water partition coefficient), typical aquatic toxicity test results (both acute and chronic endpoints), and experimental bioconcentration data. The results of this analysis support the contention of Ferguson (1948,1939) and McGowan (1952a, 1952b, 1951) that, for physical toxicity or narcosis, the chemical potency measured in the phase where toxic... 

The assumption was made that potency varied with chemical uptake, which correlated with the hydrophobicity of substituent moieties within the chemical class. Their opinion is that that the power of chemicals that act through mechanisms other than narcosis is, in part, related to their partitioning into hydrophobic biological compartments, and also is a fundamental principle for QSARs. Thus, octanol-water partition coefficients are t5q)ically working in QSARs as the chemical descriptor that comprise... 

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