3D-QSAR study of bis-azaaromatic quaternary ammonium analogs at the blood-brain barrier choline transporter

Previously, we have developed 3D-QSAR models of the blood-brain barrier (BBB) choline transporter, a transport system that may have utility as a vector for central nervous system drug delivery. In this study, we extended the model by evaluating five bis-azaaromatic quaternary ammonium compounds for their affinity for the choline binding site on the BBB-choline transporter. The compounds, and their affinities for the transporter, were then incorporated into our existing molecular model, in order to update our knowledge on the molecular recognition factors associated with interaction of ligands at the choline binding site. The current compounds are structurally related to previous substrates that we have evaluated, but offer additional three dimensional aspects compared to the series of compounds previously utilized to define the original models. The compounds showed good affinity for the BBB-choline transporter, exhibiting inhibition constants ranging from 10 to 68 μM, as determined by the in situ rat brain perfusion method. Comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) methods were used to build the new 3D QSAR models. When the new bis-azaaromatic quaternary ammonium compounds were included in the model, the best cross-validated CoMFA q² was found to be 0.536 and the non-cross-validated r² was 0.818. CoMSIA hydrophobic cross-validated q² was 0.506 and the non-cross-validated r² was 0.804. This new model was able to better predict BBB-choline transporter affinity of hemicholinium-3 (predicted 65 μM, actual 54 μM), when compared to an earlier model (predicted 316 μM).