Hydrogen bonding. 33. Factors that influence the distribution of solutes between blood and brain

It is shown that neither the set of directly determined blood-brain concentration ratios (BB) of Young and Mitchell nor the set of indirectly obtained values of Abraham and Weathersby are suitable for the construction of a general equation for the interpretation and prediction of log BB values. However, combination of both sets leads to the general equation log BB = -0.038 + 0.198R2 - 0.687 pi H2 - 0.715 alpha H2 - 0.698 beta H2 + 0.995Vx (n = 57, rho = 0.9522, sd = 0.197, F = 99.2), where the solute descriptors are R2, an excess molar refraction; pi H2, the dipolarity/polarizability, alpha H2 and beta H2, the effective or summation hydrogen-bond acidity and basicity; and Vx, the characteristic volume of McGowan. Thus solute dipolarity/polarizability, hydrogen-bond acidity, and hydrogen-bond basicity favor blood, and solute size, as Vx, favors brain. Methods are given for the estimation of solute descriptors through fragment schemes, so that log BB values themselves may be obtained simply from knowledge of solute molecular structure.