Active transport of high-affinity choline and nicotine analogs into the central nervous system by the blood-brain barrier choline transporter

摘要

Cigarette smoking is strongly implicated in the development of cardiovascular disorders.Recently identified nicotinium analogs may have therapeutic benefit as smoking cessation therapies but may have restricted entry into the centralnervous system by the blood-brain barrier (BBB) due to their physicochemical properties.Using thein situ perfusion technique,lobeline,choline,and nicotinium analogs were evaluated for binding to the BBB choline transporter.Calculated apparent K_i values ofr the choline transporter were 1.7 muM N-n-octyl choline,2.2 muM N-n-hexyl choline,27 muM N-n-decylnicotinium iodide,31.9 muM n-n-octylpyridinium iodide,49 muM N-n-octylnicotinium iodide (NONI),393 muM lobeline,and >=muM N-methylnicotiniumiodide.Nicotine and N-metylpyridinium iodide,however,donot apparetly interact with the BBB choline transporter.Given NONI's apparent K_i value determined in this study and its ability to inhibit nicotine-evoked dopamie release from superfused rat brain slices,potential brain entry of NONI via the BBB choline tansporter was evaluated.[~3H]NONI exhibited a BBB transfer coefficient value of approx1.6*10~(-3) ml/s/g and a K_m of approx250 muM.Unlabeled choline addition to the perfusion fluid reduced [~3H]NONI brainuptake.We hypothesize the N-n-octyl group on the pyridinium nitrogen of NINO may have utility as a smoking cessation cessation agents,given its ability to inhibit nAChRs mediating nicotine-evoked dopamine release centrally,and to be distriubd to brain via the BBB choline transporter.