title: Predictive screening model for potential vector-mediated transport of cationic substrates at the blood-brain barrier choline transporter.
abstract: 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 screening model was developed to aid in rational drug design/ADME of cationic nicotinic antagonists as BBB CHT ligands. Four 3D-QSAR comparative molecular field analysis (CoMFA) models were built which could predict the BBB CHT affinity for a test set with an r(2) <0.5 and cross-validated q(2) of 0.60, suggesting good predictive capability for these models. These models will allow the rapid in silico screening of binding affinity at the BBB CHT of both known nicotinic receptor antagonists and virtual compound libraries with the goal of informing the design of brain bioavailable quaternary ammonium analogs that are high affinity selective nicotinic receptor antagonists.
authors.affiliation: Department of Pharmaceutical Sciences, Texas Tech University Health Sciences Center, School of Pharmacy, Amarillo, TX 79106-1712, USA. ingo.ott@tu-bs.de
authors.forename: Werner J
authors.initials: WJ
authors.lastname: Geldenhuys
authors.forename: Vamshi K
authors.initials: VK
authors.lastname: Manda
authors.forename: Rajendar K
authors.initials: RK
authors.lastname: Mittapalli
authors.forename: Cornelis J
authors.initials: CJ
authors.lastname: Van der Schyf
authors.forename: Peter A
authors.initials: PA
authors.lastname: Crooks
authors.forename: Linda P
authors.initials: LP
authors.lastname: Dwoskin
authors.forename: David D
authors.initials: DD
authors.lastname: Allen
authors.forename: Paul R
authors.initials: PR
authors.lastname: Lockman
mesh_terms: D000818:Animals; D001692:Biological Transport / Q000502:physiology; D001812:Blood-Brain Barrier / Q000378:metabolism*; D002412:Cations; D016503:Drug Delivery Systems / Q000379:methods*; D008297:Male; D026901:Membrane Transport Proteins / Q000378:metabolism*; D008958:Models, Molecular; D011237:Predictive Value of Tests; D051381:Rats; D011916:Rats, Inbred F344; D013379:Substrate Specificity / Q000502:physiology
chemical_list: D002412:Cations; D026901:Membrane Transport Proteins; C065637:choline transporter