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 + 0.198 R(2) - 0.687 pi(2)(H) - 0.715 alpha(2)(H) - 0.698 beta(2)(H) + 0.995V(x), (n = 57, rho = 0.9522, sd = 0.197, F = 99.2), where the solute descriptors are R(2), an excess molar refraction; pi(2)(H), the dipolarity/ polarizability, alpha(2)(H) and beta(2)(H), the effective or summation hydrogen-bond acidity and basicity; and V-x, the characteristic volume of McGowan. Thus solute dipolarity/polarizability, hydrogen-bond acidity, and hydrogen-bond basicity favor blood, and solute size, as V-x, 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.