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

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 326; no. 2; p. 563
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: American Society for Pharmacology and Experimental Therapeutics 01.08.2008
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.108.136630

The current study evaluated a new series of N,N ′-alkane-diyl- bis -3-picolinium (bAPi) analogs with C 6 –C 12 methylene linkers as nicotinic acetylcholine receptor (nAChR) antagonists, for nicotine-evoked [ 3 H]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 C 6 , all analogs inhibited nicotine-evoked [ 3 H]DA overflow (IC 50 = 2 nM–6 μM; I max = 54–64%), with N,N ′ - dodecane-1,12-diyl- bis -3-picolinium dibromide (bPiDDB; C 12 ) being most potent. bPiDDB did not inhibit electrically evoked [ 3 H]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 [ 3 H]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 [ 3 H]DA overflow was not different with the combination compared with either antagonist alone, suggesting that bPiDDB interacts with α6β2-containing nAChRs. C 7 , C 8 , C 10 , and C 12 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, C 8 , C 9 , C 10 , and C 12 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.