A QSAR study of the brain/blood partition coefficients on the basis of pKa values

Abstract

A database including histamine receptor antagonists and agonists and neutral compounds, physicochemical properties and the equilibrium brain/blood concentration ratios (logBB) were analysed by using linear regression. The correlation between logBB and physicochemical properties has been remarkably improved by grouping the compounds according to their pKa values. For compounds with pKa > 8.5 logBB increases with the maximum atomic positive charge, polarity characterized by the sum of substructural partial charges and decreases with the maximum H-bond acceptor and the H-bond donor (n = 16, r2 = 0.864, s = 0.316, Q2 = 0.783). For compounds with a pKa in the range of 6.8 ≤ pKa 8.5 logBB increases with molecular size/bulk (polarizability α) and decreases with polarity and the H-bond acceptor (n = 11, r2 = 0.892, s = 0.246, Q = 0.652). For compounds with pKa < 6.8 and neutral compounds logBB increases with polarizability and and decreases with the H-bond acceptor (n = 28, r2 = 0.869, s = 0.162, Q2 = 0.820). logBB of the compounds with high pKa can be also described by logP defined as the difference between logP values measured in 1-octanol water and those measured in alkane water well, whilst logBB of the neutral compounds and the compounds with low pKa values can be also described by logP(1-octanol/water) very well, and it seems to be neither logP nor logP can describe logBB of the compounds with intermediate pKa values. These show that the compounds in three groups have different interaction mechanism in brain. © 2006 WILEY-VCH Verlag GmbH & Co. KGaA.