Carrier-mediated transport of the quaternary ammonium neuronal nicotinic receptor antagonist N,N′-dodecylbispicolinium dibromide at the blood-brain barrier

The quaternary ammonium compound N,N′-dodecyl-bispicolinium dibromide (bPiDDB) potently and selectively inhibits nicotinic receptors (nAChRs) mediating nicotine-evoked [³H]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 [³H]choline, [³H]NONI, and [¹⁴C]bPiDDB was evaluated using in situ rat brain perfusion methods. Cerebrovascular permeability surface-area product (PS) values for [³H]choline, [ ³H]NONI, and [¹⁴C]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 μM) reduced the PS of [ ³H]choline to 0.15 ± 0.06 μl/s/g (p < 0.01). Likewise, unlabeled bPiDDB (500 μM) reduced the PS of [¹⁴C]bPiDDB to 0.046 ± 0.005 μl/s/g (p < 0.01), whereas unlabeled NONI reduced the PS for [³H]NONI by approximately 50% to 0.73 ± 0.31 μl/s/g. The PS of [¹⁴C]bPiDDB was reduced (p < 0.05) in the presence of 500 μM choline, indicating that the BBB choline transporter may be responsible for the transport of bPiDDB into brain. Saturable kinetic parameters for [¹⁴C]bPiDDB were similar to those for [³H]choline. The current results suggest that bPiDDB uses the BBB choline transporter for ∼90% of its permeation into brain, and they demonstrate the carrier-mediated BBB penetration of a novel bisquaternary ammonium nAChR antagonist.