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, Michael T. Bardo

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35 Scopus citations


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.

Original languageEnglish
Pages (from-to)563-576
Number of pages14
JournalJournal of Pharmacology and Experimental Therapeutics
Issue number2
StatePublished - Aug 2008

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology


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