A set of semi-rigid cyclic and acyclic bis-quaternary ammonium analogs, which were part of a drug discovery program aimed at identifying antagonists at neuronal nicotinic acetylcholine receptors, were investigated to determine structural requirements for affinity at the blood-brain barrier choline transporter (BBB CHT). This transporter may have utility as a drug delivery vector for cationic molecules to access the central nervous system. In the current study, a virtual screeningmodel was developed to aid in rational drug design/ADME of cationic nicotinic antagonists as BBB CHT ligands. Four 3D-QSAR comp Texas Tech University Health Sciences Center,Mittapalli arative molecular field analysis (CoMFA) models were built which could predict the BBB CHT affinity for a test set with an r2 <0.5 and cross-validated q2 of 0.60, suggesting good predictive capability for these models.
February 1, 2010