Predictive screening model for potential vector-mediated transport of cationic substrates at the blood-brain barrier choline transporter

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.

Werner J. Geldenhuys, Vamshi K. Manda, Rajendar K. Mittapalli, Cornelis J. Van der Schyf, Peter A. Crooks, Linda P. Dwoskin, David D. Allen, Paul R. Lockman
February 1, 2010
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