PT - JOURNAL ARTICLE AU - Linda P. Dwoskin AU - Thomas E. Wooters AU - Sangeetha P. Sumithran AU - Kiran B. Siripurapu AU - B. Matthew Joyce AU - Paul R. Lockman AU - Vamshi K. Manda AU - Joshua T. Ayers AU - Zhenfa Zhang AU - Agripina G. Deaciuc AU - J. Michael McIntosh AU - Peter A. Crooks AU - Michael T. Bardo TI - <em>N,N</em>′-Alkane-diyl-<em>bis</em>-3-picoliniums as Nicotinic Receptor Antagonists: Inhibition of Nicotine-Evoked Dopamine Release and Hyperactivity AID - 10.1124/jpet.108.136630 DP - 2008 Aug 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 563--576 VI - 326 IP - 2 4099 - http://jpet.aspetjournals.org/content/326/2/563.short 4100 - http://jpet.aspetjournals.org/content/326/2/563.full SO - J Pharmacol Exp Ther2008 Aug 01; 326 AB - 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. The American Society for Pharmacology and Experimental Therapeutics