Abstract
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.
Footnotes
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These studies were supported by National Institutes of Health Grants NS41933, DA10934, DA00399, the Burroughs Wellcome Fund, the American Foundation for Pharmaceutical Education, and Texas Tech University Health Sciences Center School of Pharmacy. The University of Kentucky owns the patent on NONI, and a royalty stream may become available to L.P.D. and P.A.C. through University arrangements.
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DOI: 10.1124/jpet.102.045856
- Abbreviations:
- BBB
- blood-brain barrier
- CNS
- central nervous system
- NONI
- N-n-octylnicotinium iodide
- NMPI
- N-methylpyridinium iodide
- NOPI
- N-n-octylpyridinium iodide
- NMNI
- N-methylnicotinium iodide
- NBNI
- N-n-butylnicotinium iodide
- NDNI
- N-n-decylnicotinium iodide
- PA
- permeability-surface area products
- Received October 21, 2002.
- Accepted November 26, 2002.
- The American Society for Pharmacology and Experimental Therapeutics
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