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Research ArticleNEUROPHARMACOLOGY

N,N′-Alkane-diyl-bis-3-picoliniums as Nicotinic Receptor Antagonists: Inhibition of Nicotine-Evoked Dopamine Release and Hyperactivity

Linda P. Dwoskin, Thomas E. Wooters, Sangeetha P. Sumithran, Kiran B. Siripurapu, B. Matthew Joyce, Paul R. Lockman, Vamshi K. Manda, Joshua T. Ayers, Zhenfa Zhang, Agripina G. Deaciuc, J. Michael McIntosh, Peter A. Crooks and Michael T. Bardo
Journal of Pharmacology and Experimental Therapeutics August 2008, 326 (2) 563-576; DOI: https://doi.org/10.1124/jpet.108.136630
Linda P. Dwoskin
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Thomas E. Wooters
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Sangeetha P. Sumithran
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Kiran B. Siripurapu
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B. Matthew Joyce
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Paul R. Lockman
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Vamshi K. Manda
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Joshua T. Ayers
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Zhenfa Zhang
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Agripina G. Deaciuc
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J. Michael McIntosh
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Peter A. Crooks
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Michael T. Bardo
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Abstract

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 α4β2* (* indicates putative nAChR subtype assignment) and α7* 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 μM; 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 α-conotoxin MII-sensitive α6β2-containing nAChRs, slices were exposed concomitantly to maximally effective concentrations of bPiDDB (10 nM) and α-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 α6β2-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.

Footnotes

  • This research was supported by National Institutes of Health Grants K02 DA00399, T32 DA007304, and U19 DA017548.

  • Potential royalty payments to L.P.D., P.A.C., and J.T.A. may occur consistent with the University of Kentucky policy.

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

  • doi:10.1124/jpet.108.136630.

  • ABBREVIATIONS: nAChR, neuronal nicotinic acetylcholine receptor; DA, dopamine; DHβE, dihydro-β-erythroidine; α-CtxMII, α-conotoxin MII; bAPi, N,N′-alkane-diyl-bis-3-picolinium; bPiDDB, N,N′-dodecane-1,12-diyl-bis-3-picolinium dibromide; BBB, blood-brain barrier; GBR 12909, 1-[2-(bis[4-fluorophenyl]methoxy)ethyl]-4-[3-phenylpropyl]piperazine dihydrochloride; BSA, bovine serum albumin; DEC, decamethonium bromide; HEX, hexamethonium chloride; MLA, methyllycaconitine; TBC, d-tubocurarine; bPiOI, N,N′-octane-1,8-diyl-bis-3-picolinium diiodide; DAT, dopamine transporter; FR, fixed ratio; dr, dose ratio; ANOVA, analysis of variance; PS, permeability-surface area product; bPiNB, N,N′-nonane-1,9-diyl-bis-3-picolinium dibromide; bPiUB, N,N′-undecane-1,11-diyl-bis-3-picolinium dibromide; bPiDI, N,N′-decane-1,10-diyl-bis-3-picolinium diiodide; bPiHpB, N,N′-heptane-1,7-diyl-bis-3-picolinium dibromide; bPiHxI, N,N′-hexane-1,6-diyl-bis-3-picolinium diiodide; S, saline.

    • Received January 16, 2008.
    • Accepted May 5, 2008.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 326 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 326, Issue 2
1 Aug 2008
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Research ArticleNEUROPHARMACOLOGY

N,N′-Alkane-diyl-bis-3-picoliniums as Nicotinic Receptor Antagonists: Inhibition of Nicotine-Evoked Dopamine Release and Hyperactivity

Linda P. Dwoskin, Thomas E. Wooters, Sangeetha P. Sumithran, Kiran B. Siripurapu, B. Matthew Joyce, Paul R. Lockman, Vamshi K. Manda, Joshua T. Ayers, Zhenfa Zhang, Agripina G. Deaciuc, J. Michael McIntosh, Peter A. Crooks and Michael T. Bardo
Journal of Pharmacology and Experimental Therapeutics August 1, 2008, 326 (2) 563-576; DOI: https://doi.org/10.1124/jpet.108.136630

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Research ArticleNEUROPHARMACOLOGY

N,N′-Alkane-diyl-bis-3-picoliniums as Nicotinic Receptor Antagonists: Inhibition of Nicotine-Evoked Dopamine Release and Hyperactivity

Linda P. Dwoskin, Thomas E. Wooters, Sangeetha P. Sumithran, Kiran B. Siripurapu, B. Matthew Joyce, Paul R. Lockman, Vamshi K. Manda, Joshua T. Ayers, Zhenfa Zhang, Agripina G. Deaciuc, J. Michael McIntosh, Peter A. Crooks and Michael T. Bardo
Journal of Pharmacology and Experimental Therapeutics August 1, 2008, 326 (2) 563-576; DOI: https://doi.org/10.1124/jpet.108.136630
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