Optimum blood-brain barrier

Pan, D., Iyer, M., Liu, J., Li, Y., Hopfinger, A. J., Constructing optimum blood brain barrier QSAR models using a combination of 4D-molecular similarity measures and cluster analysis descriptors. J. Chem. Inf. Model. 2004, 44, 2083-2098. 

Clonidine reduces blood pressure by acting on the central nervous system, but it also contracts blood vessels in the peripheral nervous system, and this leads to an increase in blood pressure. The biological activity of a series of related compounds on the central nervous system was found to correlate with the partition coefficient between octanol and water and the biological activity on the peripheral nervous system. The study indicated that there was an optimum value for the partition coefficient, and that central and peripheral nervous system activity could not be separated, suggesting that to find a drug that only acts on the central nervous system it would be necessary to try compounds unrelated to clonidine. Clonidine attaches to the same type of receptor in both the central and peripheral nervous systems — hence the correlation between central and peripheral nervous system biological activity. To attach to the receptor in the central nervous system, however, it has to cross the blood-brain barrier and thus must dissolve in lipids to reach its target. This leads to the correlation of central nervous system activity with lipid solubility. 

The concept of optimum lipophilicity of a drug for passive transport, e.g. gastrointestinal absorption or transfer through the blood-brain barrier. Nowadays many medicinal chemists are famihar with these relationships and do not any longer realize that much of our knowledge came from such analyses. 

As stated earlier, prediction is not the main goal of a QSAR analysis. Much more often general conclusions on the reduction of toxic properties, on selectivity, on optimum lipophilicity to pass the blood-brain barrier or, on the other hand, to avoid CNS side effects, are more important for the optimization of a lead structure. As it still is industrial praxis (and will remain for patent reasons) to synthesize and test large numbers of closely related analogs, QSAR is also an important tool to decide when to stop a synthetic program (compare e.g. eqs. 178, 179 chapter 7.4) [786, 1095]. 

Thus, the conclusions from equation (27) are that the two activities cannot be separated, but for optimum hypotensive activity the lipophilicity of the compounds should be around 1.5. Such analogs can readily cross the blood-brain barrier and their central effect will override the peripheral effect. All other attempts to find chemically related analogs with improved selectivity must fail. Thus, no more syntheses and testing of compounds within this series need to be performed. Several other examples are known where desired activities have been compared with toxicides, especially for antitumor drugs. In some cases the syntheses of further analogs were stopped because no better therapeutic indices could be expected. " ... 

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