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NEUROPHARMACOLOGY

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

Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, Kentucky (L.P.D., S.P.S., K.B.S., B.M.J., J.T.A., Z.Z., A.G.D., P.A.C.); Department of Psychology, College of Arts and Sciences, University of Kentucky, Lexington, Kentucky (T.E.W., M.T.B.); School of Pharmacy, Texas Tech University of Health Sciences, Amarillo, Texas (P.R.L., V.K.M.); and Departments of Pharmaceutical Sciences, Psychiatry, and Biology, University of Utah, Salt Lake City, Utah (J.M.M.)

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 4β2* (* indicates putative nAChR subtype assignment) and 7* 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; I_max = 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 -conotoxin MII-sensitive 6β2-containing nAChRs, slices were exposed concomitantly to maximally effective concentrations of bPiDDB (10 nM) and -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 6β2-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.

Address correspondence to: Dr. Linda P. Dwoskin, Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536-0082. E-mail: ldwoskin{at}email.uky.edu