title: N,N'-Alkane-diyl-bis-3-picoliniums as nicotinic receptor antagonists: inhibition of nicotine-evoked dopamine release and hyperactivity.
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 alpha4beta2* (* indicates putative nAChR subtype assignment) and alpha7* 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 microM; 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 alpha-conotoxin MII-sensitive alpha6beta2-containing nAChRs, slices were exposed concomitantly to maximally effective concentrations of bPiDDB (10 nM) and alpha-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 alpha6beta2-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.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536-0082, USA. ldwoskin@email.uky.edu
authors.forename: Linda P
authors.initials: LP
authors.lastname: Dwoskin
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Wooters
authors.forename: Sangeetha P
authors.initials: SP
authors.lastname: Sumithran
authors.forename: Kiran B
authors.initials: KB
authors.lastname: Siripurapu
authors.forename: B Matthew
authors.initials: BM
authors.lastname: Joyce
authors.forename: Paul R
authors.initials: PR
authors.lastname: Lockman
authors.forename: Vamshi K
authors.initials: VK
authors.lastname: Manda
authors.forename: Joshua T
authors.initials: JT
authors.lastname: Ayers
authors.forename: Zhenfa
authors.initials: Z
authors.lastname: Zhang
authors.forename: Agripina G
authors.initials: AG
authors.lastname: Deaciuc
authors.forename: J Michael
authors.initials: JM
authors.lastname: McIntosh
authors.forename: Peter A
authors.initials: PA
authors.lastname: Crooks
authors.forename: Michael T
authors.initials: MT
authors.lastname: Bardo
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001693:Biological Transport, Active; D001812:Blood-Brain Barrier / Q000378:metabolism; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004193:Discrimination Learning / Q000187:drug effects; D004298:Dopamine / Q000378:metabolism; D008297:Male; D015394:Molecular Structure; D009043:Motor Activity / Q000187:drug effects; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009538:Nicotine / Q000494:pharmacology*; D018733:Nicotinic Antagonists / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D010847:Picolines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D050480:Plasma Membrane Neurotransmitter Transport Proteins / Q000378:metabolism; D011485:Protein Binding; D051381:Rats; D011916:Rats, Inbred F344; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: C513964:N,N'-dodecane-1,12-diyl-bis-3-picolinium dibromide; D009419:Nerve Tissue Proteins; D018733:Nicotinic Antagonists; D010847:Picolines; D050480:Plasma Membrane Neurotransmitter Transport Proteins; D011978:Receptors, Nicotinic; C075746:Slc6a8 protein, rat; D009538:Nicotine; D004298:Dopamine