bPiDDB

The novel nicotinic receptor antagonist, N,N'-dodecane-1,12-diyl-bis-3-picolinium dibromide (bPiDDB), inhibits nicotine-evoked [(3)H]norepinephrine overflow from rat hippocampal slices.[Pubmed:19631612]

Biochem Pharmacol. 2009 Oct 1;78(7):889-97.

Smoking is a significant health concern and strongly correlated with clinical depression. Depression is associated with decreased extracellular NE concentrations in brain. Smokers may be self-medicating and alleviating their depression through nicotine stimulated norepinephrine (NE) release. Several antidepressants inhibit NE transporter (NET) function, thereby augmenting extracellular NE concentrations. Antidepressants, such as bupropion, also inhibit nicotinic receptor (nAChR) function. The current study determined if a recently discovered novel nAChR antagonist, N,N'-dodecane-1,12-diyl-bis-3-picolinium dibromide (bPiDDB), inhibits nicotine-evoked NE release from superfused rat hippocampal slices. Previous studies determined that bPiDDB potently (IC(50)=2 nM) inhibits nicotine-evoked striatal [(3)H]dopamine (DA) release in vitro, nicotine-evoked DA release in nucleus accumbens in vivo, and nicotine self-administration in rats. In the current study, nicotine stimulated [(3)H]NE release from rat hippocampal slices (EC(50)=50 microM). bPiDDB inhibited (IC(50)=430 nM; I(max)=90%) [(3)H]NE release evoked by 30 microM nicotine. For comparison, the nonselective nAChR antagonist, mecamylamine, and the alpha7 antagonist, methyllycaconitine, also inhibited nicotine-evoked [(3)H]NE release (IC(50)=31 and 275 nM, respectively; I(max)=91% and 72%, respectively). Inhibition by bPiDDB and mecamylamine was not overcome by increasing nicotine concentrations; Schild regression slope was different from unity, consistent with allosteric inhibition. Thus, bPiDDB was 200-fold more potent inhibiting nAChRs mediating nicotine-evoked [(3)H]DA release from striatum than those mediating nicotine-evoked [(3)H]NE release from hippocampus.

The effects of a novel nicotinic receptor antagonist N,N-dodecane-1,12-diyl-bis-3-picolinium dibromide (bPiDDB) on acute and repeated nicotine-induced increases in extracellular dopamine in rat nucleus accumbens.[Pubmed:17097117]

Neuropharmacology. 2007 Mar;52(3):755-63.

The present study examined the effects of the novel nicotinic acetylcholine receptor (nAChR) antagonist, N,N'-dodecane-1,12-diyl-bis-3-picolinium dibromide (bPiDDB), after acute and repeated nicotine treatment on extracellular dopamine (DA) levels in rat nucleus accumbens (NAcc), using in vivo microdialysis. Acute nicotine (0.4mg/kg, sc) injection produced an increase (232% of basal) in extracellular DA, which was attenuated by pretreatment with the nAChR antagonist mecamylamine (4mg/kg, sc). Pretreatment with bPiDDB (1 or 3mg/kg, sc) dose-dependently reduced the increase in extracellular DA produced by nicotine (0.4mg/kg, sc), but not by amphetamine (0.5mg/kg, sc). Basal levels of NAcc DA increased in animals that had been pretreated with nicotine (0.4mg/kg, sc) for 5 days compared to saline. In addition, nicotine challenge further increased extracellular DA (237% of basal). The increase in DA in NAcc following repeated nicotine was blocked by pretreatment with mecamylamine (4mg/kg, sc) and bPiDDB (1 or 3mg/kg, sc). These results indicate that bPiDDB likely acts as an antagonist at neuronal nAChRs to inhibit DA release in NAcc after acute or repeated nicotine administration. The ability of bPiDDB to inhibit the effect of nicotine in NAcc, combined with previous studies showing decreased nicotine self-administration in rats provides support for bPiDDB as a potential lead compound for the development of a novel pharmacotherapy for nicotine dependence.

Repeated nicotine administration robustly increases bPiDDB inhibitory potency at alpha6beta2-containing nicotinic receptors mediating nicotine-evoked dopamine release.[Pubmed:20346923]

Biochem Pharmacol. 2010 Aug 1;80(3):402-9.

The novel nicotinic receptor (nAChR) antagonist, N,N'-dodecane-1,12-diyl-bis-3-picolinium dibromide (bPiDDB), and its chemically reduced analog, r-bPiDDB, potently inhibit nicotine-evoked dopamine (DA) release from rat striatal slices. Since tobacco smokers self-administer nicotine repeatedly, animal models incorporating repeated nicotine treatment allow for mechanistic evaluation of therapeutic candidates following neuroadaptive changes. The current study determined the ability of bPiDDB, r-bPiDDB and alpha-conotoxin MII (alpha-CtxMII), a peptide antagonist selective for alpha6beta2-containing nAChRs, to inhibit nicotine-evoked [(3)H]DA release from striatal slices from rats repeatedly administered nicotine (0.4mg/kg for 10 days) or saline (control). Concomitant exposure to maximally effective concentrations of r-bPiDDB (1nM) and alpha-CtxMII (1nM) resulted in inhibition of nicotine-evoked [(3)H]DA release no greater than that produced by either antagonist alone, suggesting that r-bPiDDB inhibits alpha6beta2-containing nAChRs. Repeated nicotine treatment increased locomotor activity, demonstrating behavioral sensitization. Concentration-response curves for nicotine-evoked [(3)H]DA release were not different between nicotine-treated and control groups. Maximal inhibition for alpha-CtxMII was greater following repeated nicotine compared to control (I(max)=90% vs. 62%), with no change in potency. bPiDDB was 3-orders of magnitude more potent in inhibiting nicotine-evoked [(3)H]DA release in nicotine-treated rats compared to control rats (IC(50)=5pM vs. 6nM), with no change in maximal inhibition. Neither a shift to the left in the concentration response nor a change in maximal inhibition was observed for r-bPiDDB following repeated nicotine. Thus, repeated nicotine treatment may differentially regulate the stoichiometry, conformation and/or composition of alpha6beta2-containing nAChRs mediating nicotine-evoked striatal DA release. Therefore, bPiDDB and r-bPiDDB appear to target different alpha6beta2-containing nAChR subtypes.

N,N'-Alkane-diyl-bis-3-picoliniums as nicotinic receptor antagonists: inhibition of nicotine-evoked dopamine release and hyperactivity.[Pubmed:18460644]

J Pharmacol Exp Ther. 2008 Aug;326(2):563-76.

The current study evaluated a new series of N,N'-alkane-diyl-bis-3-picolinium (bAPi) analogs with C6-C12 methylene linkers as nicotinic acetylcholine receptor (nAChR) antagonists, for nicotine-evoked [3H]dopamine (DA) overflow, for blood-brain barrier choline transporter affinity, and for attenuation of discriminative stimulus and locomotor stimulant effects of nicotine. bAPi analogs exhibited little affinity for alpha4beta2* (* indicates putative nAChR subtype assignment) and alpha7* high-affinity ligand binding sites and exhibited no inhibition of DA transporter function. With the exception of C6, all analogs inhibited nicotine-evoked [3H]DA overflow (IC50 = 2 nM-6 microM; Imax = 54-64%), with N,N'-dodecane-1,12-diyl-bis-3-picolinium dibromide (bPiDDB; C12) being most potent. bPiDDB did not inhibit electrically evoked [3H]DA overflow, suggesting specific nAChR inhibitory effects and a lack of toxicity to DA neurons. Schild analysis suggested that bPiDDB interacts in an orthosteric manner at nAChRs mediating nicotine-evoked [3H]DA overflow. To determine whether bPiDDB interacts with alpha-conotoxin MII-sensitive alpha6beta2-containing nAChRs, slices were exposed concomitantly to maximally effective concentrations of bPiDDB (10 nM) and alpha-conotoxin MII (1 nM). Inhibition of nicotine-evoked [3H]DA overflow was not different with the combination compared with either antagonist alone, suggesting that bPiDDB interacts with alpha6beta2-containing nAChRs. C7, C8, C10, and C12 analogs exhibited high affinity for the blood-brain barrier choline transporter in vivo, suggesting brain bioavailability. Although none of the analogs altered the discriminative stimulus effect of nicotine, C8, C9, C10, and C12 analogs decreased nicotine-induced hyperactivity in nicotine-sensitized rats, without reducing spontaneous activity. Further development of nAChR antagonists that inhibit nicotine-evoked DA release and penetrate brain to antagonize DA-mediated locomotor stimulant effects of nicotine as novel treatments for nicotine addiction is warranted.

Region-specific effects of N,N'-dodecane-1,12-diyl-bis-3-picolinium dibromide on nicotine-induced increase in extracellular dopamine in vivo.[Pubmed:18059317]

Br J Pharmacol. 2008 Feb;153(4):792-804.

BACKGROUND AND PURPOSE: Systemic administration of N,N'-dodecane-1,12-diyl-bis-3-picolinium dibromide (bPiDDB), an antagonist of nicotinic acetylcholine receptors (nAChRs) attenuated the nicotine-induced increase in dopamine levels in nucleus accumbens (NAcc). EXPERIMENTAL APPROACH: Using in vivo microdialysis, we investigated the effects of local perfusion of the novel nAChR antagonist bPiDDB into the NAcc or ventral tegmental area (VTA) on increased extracellular dopamine in NAcc, induced by systemic nicotine. We also examined the concentration-dependent effects of bPiDDB on the acetylcholine (ACh)-evoked response of specific recombinant neuronal nAChR subtypes expressed in Xenopus oocytes, using electrophysiological methods. KEY RESULTS: Nicotine (0.4 mg kg(-1), s.c.) increased extracellular dopamine in NAcc, which was attenuated by intra-VTA perfusion of mecamylamine (100 microM). Intra-VTA perfusion of bPiDDB (1 and 10 microM) reduced nicotine-induced increases in extracellular dopamine in NAcc. In contrast, intra-NAcc perfusion of bPiDDB (1 or 10 microM) failed to alter the nicotine-induced increase in dopamine in NAcc. Intra-VTA perfusion of bPiDDB alone did not alter basal dopamine levels, compared to control, nor the increased dopamine in NAcc following amphetamine (0.5 mg kg(-1), s.c.). Using Xenopus oocytes, bPiDDB (0.01-100 microM) inhibited the response to ACh on specific combinations of rat neuronal nAChR subunits, with highest potency at alpha3beta4beta3 and lowest potency at alpha6/3beta2beta3. CONCLUSIONS AND IMPLICATIONS: bPiDDB-Sensitive nAChRs involved in regulating nicotine-induced dopamine release are located in the VTA, rather than in the NAcc. As bPiDDB has properties different from the prototypical nAChR antagonist mecamylamine, further development may lead to novel nAChR antagonists for the treatment of tobacco dependence.