title: bis-Pyridinium cyclophanes: novel ligands with high affinity for the blood-brain barrier choline transporter.
abstract: A series of bis-pyridinium cyclophane analogs designed as conformationally restricted bis-quaternary ammonium compounds were evaluated for their affinity for the blood-brain barrier (BBB) choline transporter. All the cyclophanes investigated exhibited high affinity compared to choline. Of these compounds, N, N'-(1,10-decanediyl)3,3'-(1,9-decadiyn-1,10-diyl)-bis-pyridinium diiodide (5c) and N,N'-(1,9-nonanediyl)3,3'-(1,9-decadiyn-1,10-diyl)-bis-pyridinium dibromide (5b) exhibited highest affinity with K(i) values of 0.8 microM and 1.4 microM, respectively, and constitute some of the most potent BBB choline transporter ligands reported.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536, USA.
authors.forename: Zhenfa
authors.initials: Z
authors.lastname: Zhang
authors.forename: Paul R
authors.initials: PR
authors.lastname: Lockman
authors.forename: Rajendar K
authors.initials: RK
authors.lastname: Mittapalli
authors.forename: David D
authors.initials: DD
authors.lastname: Allen
authors.forename: Linda P
authors.initials: LP
authors.lastname: Dwoskin
authors.forename: Peter A
authors.initials: PA
authors.lastname: Crooks
mesh_terms: D001692:Biological Transport; D001812:Blood-Brain Barrier / Q000187:drug effects*; D001952:Bridged-Ring Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D002794:Choline / Q000737:chemistry; D015195:Drug Design; D006801:Humans; D007700:Kinetics; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D026901:Membrane Transport Proteins / Q000737:chemistry* / Q000378:metabolism; D008956:Models, Chemical; D008968:Molecular Conformation; D011725:Pyridines / Q000737:chemistry*; D011726:Pyridinium Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D000644:Quaternary Ammonium Compounds / Q000737:chemistry
chemical_list: D001952:Bridged-Ring Compounds; D008024:Ligands; D026901:Membrane Transport Proteins; D011725:Pyridines; D011726:Pyridinium Compounds; D000644:Quaternary Ammonium Compounds; C065637:choline transporter; D002794:Choline; C023666:pyridine
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