Carrier-mediated transport of the quaternary ammonium neuronal nicotinic receptor antagonist n,n'-dodecylbispicolinium dibromide at the blood-brain barrier
| Autor: | Linda P. Dwoskin, Zaineb A.F. Albayati, Werner J. Geldenhuys, Rajendar K. Mittapalli, David D. Allen, Vamshi K. Manda, Peter A. Crooks, Fancy Thomas, Paul R. Lockman |
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| Rok vydání: | 2007 |
| Předmět: |
Male
Stereochemistry medicine.drug_class Nerve Tissue Proteins Nicotinic Antagonists Receptors Nicotinic Blood–brain barrier Plasma Membrane Neurotransmitter Transport Proteins Choline chemistry.chemical_compound Dopamine medicine Animals Pharmacology biology Membrane transport protein Chemistry Antagonist Receptor antagonist Rats Inbred F344 Rats Choline transporter medicine.anatomical_structure Nicotinic agonist Blood-Brain Barrier Picolines biology.protein Biophysics Molecular Medicine medicine.drug |
| Zdroj: | The Journal of pharmacology and experimental therapeutics. 324(1) |
| ISSN: | 1521-0103 |
| Popis: | The quaternary ammonium compound N,N'-dodecyl-bispicolinium dibromide (bPiDDB) potently and selectively inhibits nicotinic receptors (nAChRs) mediating nicotine-evoked [(3)H]dopamine release and decreases nicotine self-administration, suggesting that this polar, charged molecule penetrates the blood-brain barrier (BBB). This report focuses on 1) BBB penetration of bPiDDB; 2) the mechanism of permeation; and 3) comparison of bPiDDB to the cations choline and N-octylnicotinium iodide (NONI), both of which are polar, charged molecules that undergo facilitated BBB transport. The BBB permeation of [(3)H]choline, [(3)H]NONI, and [(14)C]bPiDDB was evaluated using in situ rat brain perfusion methods. Cerebrovascular permeability surface-area product (PS) values for [(3)H]choline, [(3)H]NONI, and [(14)C]bPiDDB were comparable (1.33 +/- 0.1, 1.64 +/- 0.15, and 1.3 +/- 0.3 ml/s/g, respectively). To ascertain whether penetration was saturable, unlabeled substrate was added to the perfusion fluid. Unlabeled choline (500 microM) reduced the PS of [(3)H]choline to 0.15 +/- 0.06 microl/s/g (p0.01). Likewise, unlabeled bPiDDB (500 microM) reduced the PS of [(14)C]bPiDDB to 0.046 +/- 0.005 microl/s/g (p0.01), whereas unlabeled NONI reduced the PS for [(3)H]NONI by approximately 50% to 0.73 +/- 0.31 microl/s/g. The PS of [(14)C]bPiDDB was reduced (p0.05) in the presence of 500 microM choline, indicating that the BBB choline transporter may be responsible for the transport of bPiDDB into brain. Saturable kinetic parameters for [(14)C]bPiDDB were similar to those for [(3)H]choline. The current results suggest that bPiDDB uses the BBB choline transporter for approximately 90% of its permeation into brain, and they demonstrate the carrier-mediated BBB penetration of a novel bisquaternary ammonium nAChR antagonist. |
| Databáze: | OpenAIRE |
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