Prediction of Blood-Brain Barrier Penetration of meta-/para-Alkoxyphenylcarbamic Acid Esters Bearing Substituted N-Phenylpiperazine Fragment

Abstract

The present study deals with blood-brain barrier (BBB) passive penetration of the substances labelled
as 7a–7d and chemically referred to as 1-[3-(Y-alkoxyphenylcarbamoyloxy)-2-hydroxypropyl]-4-(2-methylphenyl)
piperazinium chlorides. Following their chemical structures, they could be classified as prospective α-/β-adrenoceptor
blockers. Such groups are known, among others, by their adverse reactions on central nervous system due to their
transport across the BBB. The lipophilicity as the main parameter of the BBB permeability predictions is presented by
the values of partition coefficient which was experimentally estimated using shake-flask method in two different
partitions, i.e. in octan-1-ol/buffer and cyclohexane/buffer as well. The in silico models which were used are based on
the correlation between the log BB and the Δ log P readouts (the log P value estimated in octan-1-ol/buffer minus the
one estimated in cyclohexane/buffer) whereby log BB is primary transfer marker for such compounds entering brain
from blood. Besides the log BB outputs, some other molecular physicochemical descriptors have to be generated.
According to the results obtained by using Young, Kaliszan, Kelder, Clarks, Pan, Abraham, Feher and van de
Waterbeemd models, probably none of the currently investigated compounds will permeate across the BBB.