Carrier-Mediated Transport of the Quaternary Ammonium Neuronal Nicotinic Receptor Antagonist N,N′-Dodecylbispicolinium Dibromide at the Blood-Brain Barrier

Abstract

The quaternary ammonium compound N,NЈ-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. 3 H]choline. The current results suggest that bPiDDB uses the BBB choline transporter for ϳ90% of its permeation into brain, and they demonstrate the carrier-mediated BBB penetration of a novel bisquaternary ammonium nAChR antagonist.

Nicotinic Receptor Antagonists as Treatments for Nicotine Abuse

“…We considered bPiDDB to be an important lead candidate for further study, since it had high potency and selectivity at the nAChR mediating nicotine-evoked DA release and, like NONI, was an excellent substrate for the blood–brain barrier choline transporter (i.e., brain-bioavailable). bPiDDB exhibited the following saturable blood–brain barrier penetration parameters— V max = 4.3±1.0 nmol/min/g, K m = 5±2µM, and K d = 1.1 ±0.06 × 10 −4 ml/g—which are comparable to choline (Lockman et al, 2008). Additionally, we also found that bPiDDB diminished nicotine self-administration in proof-of-concept in vivo studies (Fig.…”

“…More importantly, the N-n -alkylnicotinium analogs as a group were found to have good affinity for the blood–brain barrier choline transporter, and [ 3 H]-NONI was shown to act as a substrate for this transporter in brain uptake studies in the rat. NONI exhibited the following saturable blood–brain barrier penetration parameters— V max = 603 ± 80 nmol/min/g, K m + 661± 75 µM, and K d = 7.3±3.1 × 10 −4 ml/g—compared to choline, V max = 3±0.3 nmol/ min/g, K m = 42±6µM, and K d = 1.0±0.06 × 10 −4 ml/g (Crooks et al, 2004; Lockman et al, 2008), indicating that this molecule, although cationic and polar, is brain-bioavailable. However, the general lack of selectivity of this class of analogs for α6β2* nAChRs prompted us to explore other structural modifications of the nicotine molecule.…”

Scientific overview: 2013 BBC plenary symposium on tobacco addiction

“…Though lacking selectivity, NONI exhibited good antagonist potency at α6β2* nAChRs (IC 50 = 0.62 mM) (Crooks et al, 2004). NONI was also found to have good affinity for the BBB choline transporter (Crooks et al, 2004; Dwoskin et al, 2004; Lockman et al, 2008), suggesting good brain bioavailability due to its cationic quaternary ammonium structure.…”

“…The most potent among them was bPiDDB ( N , N ′-dodecane-1,12-diyl- bis -3-picolinium dibromide; Fig. 2) (IC 50 = 5 nM; Imax = 60% at α6β2*-containing nAChRs) - which had little or no affinity for either α4β2* or α7* nAChRs (Crooks et al, 2004; Dwoskin et al, 2004), and was an excellent substrate for the BBB choline transporter (Lockman et al, 2008). Pharmacokinetic studies carried out in rats treated with 14 C-bPiDDB confirmed its brain bioavailability (Albayati et al, 2008).…”

Bis-azaaromatic quaternary ammonium salts as antagonists at nicotinic receptors mediating nicotine-evoked dopamine release: An investigation of binding conformation

“…24 nature and polarity of the molecule, bPiDDB is brain bioavailable, due to its facilitated transport via the blood-brain barrier choline transporter. 25 Moreover, behavioral studies in rats showed that bPiDDB dose-dependently decreased intravenous nicotine selfadministration, but not sucrose-maintained responding, suggesting a specific inhibition of nicotine reward. 26 Taken together, bPiDDB and its analogues represent lead compounds for the development of a new class of therapeutic agents for the treatment of tobacco dependence.…”