Central nervous system lipophilic properties

Hansch and Leo [13] described the impact of Hpophihdty on pharmacodynamic events in detailed chapters on QSAR studies of proteins and enzymes, of antitumor drugs, of central nervous system agents as well as microbial and pesticide QSAR studies. Furthermore, many reviews document the prime importance of log P as descriptors of absorption, distribution, metabolism, excretion and toxicity (ADMET) properties [5-18]. Increased lipophilicity was shown to correlate with poorer aqueous solubility, increased plasma protein binding, increased storage in tissues, and more rapid metabolism and elimination. Lipophilicity is also a highly important descriptor of blood-brain barrier (BBB) permeability [19, 20]. Last, but not least, lipophilicity plays a dominant role in toxicity prediction [21]. 

Obviously, these findings confirm the theoretical assumption that the lipophilic properties of sulfur mustard result in a distribution, primarily in lipophilic tissues. High concentrations found in the brain may also explain why the central nervous system is one of the organs exhibiting systemic effects of sulfur mustard poisoning, even though it is not a site of rapidly proliferating cells. 

The parent compound of the secoiridoids is secologa-nin (see secoiridoids), the most important intermediate in the biogenesis of alkaloids that are not derived from an amino acid. This includes most indole alkaloids, the ipecac, the Cinchona, and the pyrroloquinoline alkaloids as well as simple monoterpene alkaloids The best known biological property of the I. is their bitter taste. However, bitter principles are mostly not used as pure substances, instead alcoholic extracts are preferred to stimulate appetite (increased secretion of gastric juice). Furthermore, bitter substances are used to modify the taste of pharmaceutical products. Some I. exert various effects on the central nervous system as a consequence of their volatility and lipophilicity, e.g., nepetalactone, iridodial, teucrium lactones, and valepotriates. 

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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