RT Journal Article
SR Electronic
T1 Active Transport of High-Affinity Choline and Nicotine Analogs into the Central Nervous System by the Blood-Brain Barrier Choline Transporter
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 1268
OP 1274
DO 10.1124/jpet.102.045856
VO 304
IS 3
A1 David D. Allen
A1 Paul R. Lockman
A1 Karen E. Roder
A1 Linda P. Dwoskin
A1 Peter A. Crooks
YR 2003
UL http://jpet.aspetjournals.org/content/304/3/1268.abstract
AB 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 central nervous system by the blood-brain barrier (BBB) due to their physicochemical properties. Using the in situ perfusion technique, lobeline, choline, and nicotinium analogs were evaluated for binding to the BBB choline transporter. Calculated apparent Ki values for the choline transporter were 1.7 μM N-n-octyl choline, 2.2 μM N-n-hexyl choline, 27 μMN-n-decylnicotinium iodide, 31.9 μMN-n-octylpyridinium iodide, 49 μMN-n-octylnicotinium iodide (NONI), 393 μM lobeline, and ≥1000 μM N-methylnicotinium iodide. Nicotine andN-methylpyridinium iodide, however, do not apparently interact with the BBB choline transporter. Given NONI's apparentKi value determined in this study and its ability to inhibit nicotine-evoked dopamine release from superfused rat brain slices, potential brain entry of NONI via the BBB choline transporter was evaluated. [3H]NONI exhibited a BBB transfer coefficient value of ∼1.6 × 10−3 ml/s/g and a Km of ∼250 μM. Unlabeled choline addition to the perfusion fluid reduced [3H]NONI brain uptake. We hypothesize the N-n-octyl group on the pyridinium nitrogen of NONI facilitates brain entry via the BBB choline transporter. Thus, NONI may have utility as a smoking cessation agent, given its ability to inhibit nAChRs mediating nicotine-evoked dopamine release centrally, and to be distributed to brain via the BBB choline transporter. The American Society for Pharmacology and Experimental Therapeutics