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METABOLISM, TRANSPORT, AND PHARMACOGENOMICS
Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, Texas (P.R.L., V.K.M., W.J.G., R.K.M., F.T., D.D.A.); Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, Kentucky (Z.F.A., P.A.C., L.P.D.); and Department of Pharmaceutical Sciences, Northeastern Ohio Universities College of Pharmacy, Rootstown, Ohio (W.J.G., P.A.C., L.P.D.)
Received August 27, 2007; accepted October 2, 2007.
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Abstract |
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90% of its permeation into brain, and they demonstrate the carrier-mediated BBB penetration of a novel bisquaternary ammonium nAChR antagonist.
). Currently, there are three pharmacotherapies available to help smokers overcome this addiction: 1) nicotine replacement therapies that attempt to wean the individual from nicotine; 2) buproprion, which inhibits the reuptake of dopamine and acts to antagonize neuronal nicotinic acetylcholine receptors (nAChRs) (Miller et al., 2002; Warner and Shoaib, 2005); and 3) varenicline, a recently introduced 
4β2 nAChR partial agonist (Foulds, 2006). Despite the fact that all these therapies increase extracellular dopamine levels, their overall smoking cessation failure rate at 1 year is 80% (Silagy et al., 2004), which strongly suggests that further research on the development of alternative therapies is needed.
In this respect, alternative approaches, which may afford increased efficacy as a nicotine cessation therapy, include the combination of nicotine and an nAChR antagonist to block reinforcement (Rose et al., 1994, 1998), or the use of a subtype-selective nAChR antagonist alone (Dwoskin and Crooks, 2001; Dwoskin et al., 2004). The relatively selective 7 nAChR antagonist methyllycaconitine (MLA) has been reported to reduce nicotine self-administration and alleviate nicotine withdrawal symptoms in rodents (Markou and Paterson, 2001). However, recent work has shown that [3H]MLA is not able to penetrate the rat BBB at rates sufficient to block central 7 nAChRs in nicotine-exposed animals (Turek et al., 1995; Tucci et al., 2003; Lockman et al., 2005b). In addition, MLA is an antagonist at peripheral 1-containing nAChRs (Dobelis et al., 1999; Pfister et al., 1999). Taken together, these results suggest that the dose of MLA administered during chronic nicotine exposure that would be needed to penetrate the BBB and be pharmacologically active may result in neuromuscular blockade (Lockman et al., 2005b). In addition, in clinical trials, mecamylamine, a non-selective nAChR antagonist, administered in combination with nicotine replacement has been demonstrated to increase 12-month tobacco abstinence rates by 2 to 9-fold over placebo (Rose et al., 1994, 1998). In these studies, mecamylamine doses had to be reduced, however, due to significant untoward side effects as a result of antagonism of peripheral nAChRs.
The above-mentioned limitations in the use of mecamylamine and MLA as candidate pharmacotherapies point to nAChR subtype selectivity and BBB penetration as important characteristics of new lead candidates slated for clinical development as smoking cessation agents. In this respect, we have recently synthesized a series of bisazaaromatic quaternary ammonium analogs that act as central nAChR antagonists (Ayers et al., 2002). Within this series, N,N'-dodecyl-bispicolinium dibromide (bPiDDB) (Fig. 1) potently (IC50 = 5 nM) inhibited nAChRs mediating nicotine-evoked [3H]dopamine release from rat brain striatal slices (Dwoskin et al., 2004). Recent behavioral studies have shown that s.c. administration of bPiDDB dose-dependently decreases nicotine self-administration and attenuates nicotine-induced hyperactivity in rats (Neugebauer et al., 2006), providing in vivo results consistent with the in vitro neurochemical findings described previously. Therefore, following repeated treatment with nicotine, bPiDDB seems to penetrate the BBB at concentrations that block the centrally mediated effects of nicotine. Furthermore, we have shown previously that bPiDDB has high affinity for the BBB choline transporter (Geldenhuys et al., 2005a), a known vector for CNS penetration of cationic molecules (Allen and Smith, 2001; Lockman and Allen, 2002; Allen et al., 2003).
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Materials and Methods |
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80 Ci/mmol) and [14C]sucrose (4.75 mCi/mmol) from DuPont-New England Nuclear (Boston, MA). All radiolabeled compounds were dried completely before use to eliminate possible contaminants, including [3H]H2O. Unlabeled choline chloride and components of the physiological buffer (NaCl, NaHCO3, KCl, NaH2PO4, CaCl2, MgSO4, and D-glucose) were obtained from Sigma-Aldrich (St. Louis, MO). Unlabeled NONI and bPiDDB were prepared as described previously (Wilkins et al., 2002; Dwoskin et al., 2004).
Animals. Male Fischer-344 rats (220–330 g) were obtained from Charles River Laboratories (Kingston, NY), and they were used for all experiments described herein. All studies were approved by the Animal Care and Use Committee at Texas Tech, and they were conducted in accordance with the Institute of Laboratory Animal Resources (1996).
In Situ Rat Brain Perfusion Technique. The in situ rat brain perfusion technique was used to evaluate BBB transporter uptake of [14C]bPiDDB (650 nM), [3H]NONI (300 nM), and [3H]choline (14 nM) (Takasato et al., 1984; Allen and Smith, 2001; Lockman et al., 2003). In brief, a polyethylene-60 catheter filled with heparinized saline (100 units/ml) was placed into the left common carotid artery after ligation of the left external carotid, occipital, and common carotid arteries (common carotid artery ligation was accomplished caudally to the catheter implantation site). The pterygopalatine artery was left open (Allen and Smith, 2001). Rat body temperature was monitored and maintained at 37°C by a heating pad and feedback device (YSI indicating controller; YSI Inc., Yellow Springs, OH). Buffered physiological perfusion fluid was titrated to a pH of 7.4 (osmolarity 290 mOsm) and contained 128 mM NaCl, 2.4 mM NaPO3, 29 mM NaHCO3, 4.2 mM KCl, 1.5 mM CaCl2, 0.9 mM MgCl2, and 9 mM D-glucose and combinations of [14C]bPiDDB, [3H]NONI, and [3H]choline and/or corresponding unlabeled substrates.
Immediately before perfusion, the perfusion fluid was filtered, warmed to 37°C, and gassed with 95% air and 5% CO2. Perfusion fluid was infused at 10 ml/min for 60 s into the left carotid artery via an infusion pump (Harvard Apparatus Inc., South Natick, MA). This flow rate maintained carotid artery pressure at 120 mm Hg. At time T, rats were decapitated, the brain rapidly removed from the skull, and the perfused hemisphere was dissected on ice after removal of the arachnoid membrane and meningeal vessels. Brain regions and perfusion fluid samples were digested overnight at 50°C in 1 ml of 1 M piperidine. Scintillation fluid (10 ml of Scintisafe; Fisher Scientific, Pittsburgh, PA) was added to each vial, and double channel (3H and 14C) scintillation spectrometric analysis of brain and perfusate samples was then accomplished with appropriate correction for quench, background, and efficiency (LS 6500; Beckman Coulter, Fullerton, CA).
Kinetic Analysis. Concentrations of tracer in brain and perfusion fluid were expressed as disintegrations per minute per gram of brain or disintegrations per minute per milliliter of perfusion fluid. BBB penetration was determined using the initial uptake method, as described previously (Takasato et al., 1984; Allen et al., 2003). Linear and unidirectional uptake of [14C]bPiDDB (640 nM), [3H]NONI (300 nM), and [3H]choline (14 nM) into brain was determined using 15 to 60-s perfusions. Unidirectional uptake transfer constants (Kin) were calculated from the following relationship to the linear portion of the uptake curve (eq. 1):
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):
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):
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The concentration dependence of radiolabel influx into brain was analyzed using a model with single saturable and nonsaturable components (eq. 4):
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).
Capillary Depletion. The endothelial and vascular component of [14C]bPiDDB in relation to total brain uptake was determined in rats using the capillary depletion method (Triguero et al., 1990). In brief, after a 60-s brain perfusion, rats were decapitated, and the brain was isolated quickly and placed on ice. The choroid plexi and meninges were excised. Brain tissue (50 mg wet wt) was homogenized (Polytron homogenizer; Brinkmann Instruments; Westbury, NY) in 5-ml capillary depletion buffer [containing 10 mM 4-(2-hydroxyethyl)-piperazineethane sulfonic acid, 141 mM NaCl, 4 mM KCl, 2.8 mM CaCl2, 1 mM MgSO4, 1 mM NaH2PO4, and 10 mM D-glucose, pH 7.4] and kept on ice. Ten milliliters of ice-cold 26% clinical grade dextran were added, and homogenization was repeated. Aliquots of homogenate were centrifuged at 5400g for 15 min. Capillary-depleted supernatant was separated from the vascular pellet. The homogenate, supernatant, and pellet were analyzed by beta-scintillation spectrometry. The amount of [14C]bPiDDB in the brain homogenate, supernatant, and pellet was expressed as the percentage ratio of tissue (Cbrain; disintegrations per minute per gram) to perfusate activities (Cperfusate; disintegrations per minute per milliliter). Similar methodology was used to determine brain distribution of [3H]choline and [14C]sucrose.
HPLC Determination of Radiochemical Purity of [14C] bPiDDB. All mobile phase buffers were prepared using HPLC grade reagents. All buffers were degassed before use. Chromatography was performed on an Alltima C18 column (5 µm, 150 x 3.2; Alltech Associates, Deerfield, IL). The mobile phase used was 2 mM ammonium formate/acetonitrile [60:40 v/v %], containing 0.1% heptafluorobutyric acid, and pH was adjusted to 2.3 with formic acid. The flow rate was 0.4 ml/min. [14C]bPiDDB was coinjected with an unlabeled sample of bPiDDB, which was used as a UV-detectable marker (0.1 mg/ml) for identification of the fraction eluting from the column that contained bPiDDB. Five microliters of analyte solution ([14C]bPiDDB and unlabeled bPiDDB) was injected onto the HPLC system. bPiDDB had a tR of 5.6 min. Column fractions were collected at 10-s intervals over 20 min, and they were analyzed directly for 14C content via beta scintillation spectrometry. The 14C label coeluting with the UV-visible unlabeled marker of bPiDDB was determined as a percentage of the total 14C label in all the fractions collected, and it constituted the radiochemical purity of the 14C-labeled bPiDDB.
Statistical Analysis. Data presented are from the frontal cerebral cortex, unless otherwise stated, and they are expressed as mean ± S.E.M. for n = 3 to 5 independent determinations for each compound evaluated. Data were analyzed by analysis of variance with Bonferroni correction for multiple comparisons (GraphPad Prism 4; GraphPad Software Inc., San Diego, CA). Differences between the means were considered significant at p < 0.05.
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). Control vascular volume of [14C]sucrose for 60-s perfusion was 1.20 ± 0.2 ml/g, and it was consistent with previous reports (Takasato et al., 1984; Lockman et al., 2005a,b). The addition of 50 (1.25 ± 0.2 ml/g), 100 (1.28 ± 0.1 ml/g), and 250 µM (1.30 ± 0.3 ml/g) of unlabeled bPiDDB to the perfusate did not significantly alter the vascular volume of [14C]sucrose, suggesting that integrity of the BBB was not compromised in the presence of bPiDDB at physiological doses. Subsequent experiments using [14C]bPiDDB used the calculated vascular volume from these studies to correct for [14C]bPiDDB volume of distribution (Vd). Brain Permeability of [14C]bPiDDB, [3H]NONI, and [3H]Choline. The BBB permeation of [14C]bPiDDB, [3H]NONI, and [3H]choline was evaluated using the rat brain perfusion method. Uptake was evaluated during a 15- to 60-s period, and brain/perfusion fluid ratios (i.e., Vd) were plotted as a function of time. The total cortical PS value for the nAChR antagonists [14C]bPiDDB and [3H]NONI were 1.23 ± 0.3 and 1.64 ± 0.15 µl/s/g, respectively, and they were not different from that obtained for the endogenous substrate choline (1.33 ± 0.1 µl/s/g) (Fig. 2). PS values were not different (p > 0.05) between all brain regions examined for all three compounds. Regional PS differed significantly between [3H]choline and [3H]NONI for the frontal cortex (1.26 ± 0.05 and 1.64 ± 0.15 µl/s/g, respectively; p < 0.05), parietal cortex (1.29 ± 0.05 and 1.83 ± 0.05, respectively; p < 0.05), and in the thalamus/hypothalamus region (1.06 ± 0.07 and 1.56 ± 0.16 µl/s/g; p < 0.05; Table 1). The only difference in PS values between [3H]choline and [14C]bPiDDB was noted in the caudate putamen (1.06 ± 0.03 and 1.85 ± 0.11 µl/s/g; p < 0.05).
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Because PS values for [3H]choline, [3H]NONI, and [14C] bPiDDB are permeability-limited (i.e., 10-fold less than that of compounds subject to flow-limited BBB extraction), regional alterations of BBB PS brain uptake are minimized (Lockman et al., 2005a), e.g., choline, frontal cortical PS: 1.26 ± 0.5 µl/s/g and cerebellum, 1.14 ± 0.27 µl/s/g (Table 1).
Linear Kinetics of [14C]bPiDDB at the BBB. Distribution of [14C]bPiDDB (tracer purity >99% as determined by HPLC) across the BBB was determined using brief perfusions of 20 to 60 s. Brain accumulation of tracer was linear for 60 s (Fig. 1) from which the unidirectional uptake constant Kin of 1.3 ± 0.3 µl/s/g was calculated using eq. 2.
Carrier-Mediated Uptake of [3H]Choline, [3H]NONI, and [14C]bPiDDB at the BBB. Further experiments were conducted to determine whether the addition of 500 µMof unlabeled substrate to the perfusion fluid would reduce brain PS for the corresponding radiolabeled compound (tracer concentration), which would indicate carrier-mediated brain up-take (Takasato et al., 1984; Allen and Smith, 2001; Allen et al., 2003). The addition of unlabeled choline reduced brain PS of [3H]choline to 0.15 ± 0.06 µl/s/g (p < 0.01). Likewise, the addition of unlabeled bPiDDB reduced [14C]bPiDDB PS by 10-fold to 0.046 ± 0.005 µl/s/g (p < 0.01) (Fig. 3). However, [3H]NONI PS was only reduced 45% to 0.89 ± 0.17 µl/s/g (p < 0.05) upon addition of unlabeled NONI.
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; Lockman et al., 2004). The addition of 500 µM choline did not reduce [3H]NONI brain uptake (1.24 ± 0.5 µl/s/g; p > 0.05) (Fig. 4). However, a higher choline concentration (5 mM) reduced PS for [3H]NONI (p < 0.05) to 0.75 ± 0.33 µl/s/g (data not shown). In the presence of 500 µM choline, PS for [14C]bPiDDB was reduced 90% to 0.052 ± 0.007 µl/s/g (p < 0.05), consistent with the magnitude of [3H]choline reduction after addition of unlabeled choline.
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Transport Kinetics for [14C]bPiDDB. Saturation kinetic parameters were evaluated with the addition of unlabeled choline to the perfusion fluid at concentrations of 2.5 µM to 5 mM. A dose-dependent reduction of [14C]bPiDDB PS in the presence of unlabeled choline for the frontal cortical region is shown in Fig. 5. Saturation kinetic parameters observed for [14C]bPiDDB were Km = 5.0 ± 2.0 µM, Vmax = 4.3 ± 1.0 nmol/min/g, and Kd = 11 ± 0.6 µl/s/g (Fig. 6). Similar results were obtained with [3H]NONI, and they are presented in Table 2. [3H]Choline saturation parameters are not different (p > 0.05) compared with those for [14C]bPiDDB.
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Capillary Depletion Results. The vascular component to the total brain uptake of [14C]bPiDDB, [3H]choline, and [14C]sucrose were calculated using capillary depletion (Table 3). The total Vd using the in situ perfusion at the end of 60 s was 8.5 ± 0.2, 1.6 ± 0.3, and 9.5 ± 0.4% (n = 3–5 rats) for [3H]choline, [14C]sucrose, and [14C]bPiDDB, respectively. Endothelial cell accumulation for [14C]bPiDDB was calculated to be 2.3 ± 0.4%, giving a brain accumulation of 5.8%, which is comparable with [3H]choline (5.6%). A negligible amount of [14C]sucrose had accumulated in brain during the 60-s perfusion, and endothelial accumulation was limited to 0 0.009 ± 0.003%. The results suggests that a significant fraction of [14C]bPiDDB (comparable with choline) is transported across the BBB.
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Discussion |
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). Therefore, bPiDDB possesses two characteristics—brain bioavailability and selectivity for nAChRs mediating nicotine-evoked dopamine release—that are important for development of this potential clinical candidate as a smoking cessation therapy.
The BBB restricts to a large degree the diffusion of cations from the neurovasculature compartment to the brain parenchymal space. This is primarily due to the neurovascular endothelial cells being connected to each other by a number of tight junctional and adherens proteins, such as claudin, zonulae occludens, and cingulin (Ueno, 2007). The presence of these cell-to-cell tight junctions in the neurovasculature results in an electrical resistance 100 times greater than that provided by peripheral capillary endothelium (Butt et al., 1990). This paracellular occlusion functionally restricts the blood-to-brain transfer of molecules in a manner similar to a continuous cell membrane, i.e., molecules that are lipid soluble move across the membrane, whereas hydrophilic solutes have only minimal permeation. In addition to the tight junctions, there are other BBB mechanisms that further limit drug access to brain, such as the absence of paracellular openings, the lack of pinocytosis, a high degree of enzymatic activity in capillary endothelium and significant carrier-mediated efflux (Begley and Brightman, 2003). Despite these restrictions, it has been shown that the charged quaternary ammonium molecule, choline (Fig. 1), is transported across the BBB via a saturable carrier-mediated mechanism involving the BBB choline transporter (Cornford et al., 1978; Allen and Smith, 2001). This mechanism increases the BBB permeability for choline 10-fold over the passive diffusion rate. This process is essential, considering that the brain has a high demand for choline, and the fact that the brain cannot synthesize choline de novo in sufficient amounts for cholinergic functioning (Ansell and Spanner, 1971).
The BBB choline transporter has also been shown to play a significant role in the brain uptake of other choline derivatives (Metting et al., 1998; Allen et al., 2003). The BBB choline transporter has been proposed to be suitable as a drug delivery vector for cationic drugs, considering that it has high transport capacity, has an adequate transfer rate from blood to brain, and physiological plasma concentrations of choline are only 25% of the Km value (Klein et al., 1992; Allen and Smith, 2001). In this respect, the BBB choline transporter is free to transport other cationic molecules without interrupting the supply of choline to the brain. Using a native nutrient transporter to deliver drugs into the CNS is not without precedent. For example, the large neutral amino acid BBB transporter is able to facilitate the brain permeation of baclofen, melphalan, sulfoximine, azaserine, 2-amino-3-(3,4-dihydroxyphenyl)-2-methyl-propanoic acid, and the chemotherapeutic agent DL-2-amino-7-bis[(2-chloroethyl)amino]-l,2,3,4-tetrahydro-2-naphthoic acid (Takada et al., 1992).
The choline binding site on the BBB choline transporter consists of an anionic binding region that accommodates positively charged quaternary ammonium groups or simple organic cations (Lockman and Allen, 2002). This has been confirmed in choline uptake studies using simple quaternary ammonium cations, such as tetraethylammonium and tetra-methylammonium (Simon et al., 1975). In addition, the substrate-binding domain is thought to be responsible for the competitive binding of isoarecolone and lobeline analogs (Metting et al., 1998), and procainamide, quinine, and serotonin (Pardridge and Oldendorf, 1977). Furthermore, the BBB choline transporter also binds metal cations, such as cesium, lithium, potassium, manganese, and cadmium (Allen and Smith, 2001). In summary, the BBB choline transporter seems to be rather promiscuous in binding cations that meet the minimal structural requirements for substrate recognition by the transporter (Simon et al., 1975; Lockman and Allen, 2002).
In recent studies, we have shown that the BBB choline transporter similarly binds a large number of other quaternary ammonium cations that act as nAChR antagonists. For example, N-n-alkylnicotinium analogs in which the N-n-alkyl chain varies from C1 to C8 (NONI) (Fig. 1) inhibited [3H]choline uptake, with apparent Ki values ranging from 1 mM to 49 µM. Ki values decreased with increasing length of the N-n-alkyl chain (Allen et al., 2003). In addition, by comparing binding affinities and structural features, comparative molecular field analysis predicted a BBB choline transporter affinity of 65 µM for the defining substrate hemicholinium-3, in good agreement with the experimental Ki of 54 µM (Geldenhuys et al., 2005a,b). This in silico approach is critical for accelerating the drug discovery process, because the ability of such compounds to act as substrates for the BBB choline transporter is important for establishing brain bioavailability of such cationic molecules (Geldenhuys et al., 2005a,b) before they can be considered as drug candidates for animal behavioral studies.
With regard to the current study, bPiDDB is a bisquaternary ammonium analog containing a pH-independent, positively charged nitrogen in each of the two azaaromatic rings. Brain permeability of bPiDDB by passive diffusion would be expected to be minimal. The current study demonstrates that bPiDDB undergoes facilitated saturable transport at the BBB with a permeability of 10-fold above the passive diffusion rate, similar to that for choline (Fig. 5). Similar rates of permeability for bPiDDB were found throughout all brain regions examined, with the caudate putamen being significantly higher than the other brain regions evaluated (Table 1). To understand the mechanism of bPiDDB penetration at the BBB, we ascertained that [14C]bPiDDB transport is sensitive to choline inhibition in a dose-dependent manner. These data and the data demonstrating that bPiDDB inhibits [3H]choline BBB transport (Geldenhuys et al., 2005a) strongly suggests that [14C]bPiDDB and choline not only compete for the same binding site but also compete for facilitated transport at the BBB choline transporter. Taken together, the data indicate that the BBB choline transporter facilitates the transport of bPiDDB from the neurovasculature into the brain parenchyma. However, it is possible that bPiDDB uses additional cationic transporter proteins that are also sensitive to choline inhibition.
To compare the rate and saturable kinetics of bPiDDB to another structurally related quaternary ammonium nAChR antagonist currently being evaluated in preclinical studies, we determined the saturable kinetics of NONI (Fig. 1). Although the total permeability for [3H]NONI is not different from either [14C]bPiDDB or [3H]choline (Fig. 1; Table 1), approximately 50% [3H]NONI penetrating brain following systemic administration is the result of passive diffusion, and the remaining 50% is mediated by the BBB choline transporter. However, in the case of [14C]bPiDDB and [3H]choline, only 10% of the permeation across the BBB is mediated by passive diffusion, and the other 90% is mediated by the BBB choline transporter (Table 2).
The nonquaternary ammonium nAChR antagonist MLA has been shown previously to penetrate the BBB by passive diffusion alone (Lockman et al., 2005b), but it has limited efficacy, due to BBB permeability diffusion reductions occurring during chronic nicotine exposure (Lockman et al., 2005b). It is noteworthy that it has been shown previously that choline transport at the BBB is largely unaffected during chronic nicotine exposure (Lockman et al., 2006). In this respect, it is anticipated that brain bioavailability of bPiDDB will also not be altered by chronic nicotine administration, due to its structural similarity to choline and because 90% of its brain bioavailability results from facilitated transport via the BBB choline transporter. This is of significance with respect to the potential clinical use of bPiDDB as a smoking cessation agent.
In summary, the current results coupled with our previous reports indicating that bPiDDB antagonizes neuronal nAChRs and potently inhibits nicotine-evoked dopamine release in the nucleus accumbens after acute and repeated nicotine administration (Neugebauer et al., 2006; Rahman et al., 2007), strongly suggest that bPiDDB should be considered as a lead candidate in the development of novel smoking cessation pharmacotherapies.
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Footnotes |
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
ABBREVIATIONS: nAChR, nicotinic acetylcholine receptor; MLA, methyllycaconitine; BBB, blood-brain barrier; bPiDDB, N,N'-dodecyl-bispicolinium dibromide; CNS, central nervous system; NONI, N-octylnicotinium iodide; PS, permeability product(s); HPLC, reverse phase-high-performance liquid chromatography; Vd, volume of distribution.
Address correspondence to. Dr. Paul R. Lockman, Department of Pharmaceutical Sciences, Texas Tech University Health Sciences Center, 1300 S. Coulter Dr., Amarillo, TX 79106-1712. E-mail: paul.lockman{at}ttuhsc.edu
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