title: Inhibition of choline uptake by N-cyclohexylcholine, a high affinity ligand for the choline transporter at the blood-brain barrier.
abstract: The blood-brain barrier (BBB) choline transporter (CHT) may have utility as a drug delivery vector for drugs that act in the central nervous system. Previous studies suggested the importance of hydrophobic moieties on the cationic nitrogen of choline for improved affinity for this transporter. In a pilot study, we therefore designed five novel N-cycloalkyl derivatives of choline, one of which showed promising inhibition properties. This choline analogue had a cyclohexyl (UMBB-5) moiety substituting one of the methyl groups attached to the cationic nitrogen in choline. In situ experimental data were obtained from in situ rat brain perfusion studies. The binding affinity for the BBB-choline transporter found for UMBB-5 was K(i)=1.9 microM. Comparative molecular field analysis (CoMFA) suggested that the cyclohexyl moiety orientates towards a steric favourable area. Taken together, the results of these in situ and in silico studies provide further evidence or restrictions that occur with binding to this brain drug delivery vector.
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Science Centre, Amarillo, TX 79106, USA.
authors.forename: Werner J
authors.initials: WJ
authors.lastname: Geldenhuys
authors.forename: Paul R
authors.initials: PR
authors.lastname: Lockman
authors.forename: Ashok E
authors.initials: AE
authors.lastname: Philip
authors.forename: James H
authors.initials: JH
authors.lastname: McAfee
authors.forename: Bryan L
authors.initials: BL
authors.lastname: Miller
authors.forename: Christopher R
authors.initials: CR
authors.lastname: McCurdy
authors.forename: David D
authors.initials: DD
authors.lastname: Allen
mesh_terms: D000818:Animals; D001692:Biological Transport; D001812:Blood-Brain Barrier / Q000378:metabolism*; D002794:Choline / Q000031:analogs & derivatives* / Q000378:metabolism*; D004337:Drug Carriers / Q000378:metabolism*; D008024:Ligands; D008297:Male; D008958:Models, Molecular; D015394:Molecular Structure; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D010865:Pilot Projects; D050480:Plasma Membrane Neurotransmitter Transport Proteins / Q000378:metabolism*; D011485:Protein Binding; D051381:Rats; D011916:Rats, Inbred F344; D013329:Structure-Activity Relationship
chemical_list: D004337:Drug Carriers; D008024:Ligands; C505800:N-cyclohexylcholine; D009419:Nerve Tissue Proteins; D050480:Plasma Membrane Neurotransmitter Transport Proteins; C075746:Slc6a8 protein, rat; D002794:Choline