title: bPiDI: a novel selective α6β2* nicotinic receptor antagonist and preclinical candidate treatment for nicotine abuse.
abstract: OBJECTIVE
  Nicotinic acetylcholine receptors (nAChRs) containing α6β2 subunits expressed by dopamine neurons regulate nicotine-evoked dopamine release. Previous results show that the α6β2* nAChR antagonist, N,N'-dodecane-1,12-diyl-bis-3-picolinium dibromide (bPiDDB) inhibits nicotine-evoked dopamine release from dorsal striatum and decreases nicotine self-administration in rats. However, overt toxicity emerged with repeated bPiDDB treatment. The current study evaluated the preclinical pharmacology of a bPiDDB analogue.
  
  
  METHODS
  The C₁₀ analogue of bPiDDB, N,N-decane-1,10-diyl-bis-3-picolinium diiodide (bPiDI), was evaluated preclinically for nAChR antagonist activity.
  
  
  RESULTS
  bPiDI inhibits nicotine-evoked [³H]dopamine overflow (IC₅₀= 150 nM, I(max)=58%) from rat striatal slices. Schild analysis revealed a rightward shift in the nicotine concentration-response curve and surmountability with increasing nicotine concentration; however, the Schild regression slope differed significantly from 1.0, indicating surmountable allosteric inhibition. Co-exposure of maximally inhibitory concentrations of bPiDI (1 µM) and the α6β2* nAChR antagonist α-conotoxin MII (1 nM) produced inhibition not different from either antagonist alone, indicating that bPiDI acts at α6β2* nAChRs. Nicotine treatment (0.4 mg·kg⁻¹·da⁻¹, 10 days) increased more than 100-fold the potency of bPiDI (IC₅₀=1.45 nM) to inhibit nicotine-evoked dopamine release. Acute treatment with bPiDI (1.94-5.83 µmol·kg⁻¹, s.c.) specifically reduced nicotine self-administration relative to responding for food. Across seven daily treatments, bPiDI decreased nicotine self-administration; however, tolerance developed to the acute decrease in food-maintained responding. No observable body weight loss or lethargy was observed with repeated bPiDI.
  
  
  CONCLUSIONS
  These results are consistent with the hypothesis that α6β2* nAChR antagonists have potential for development as pharmacotherapies for tobacco smoking cessation.
authors.affiliation: Department of Psychology, College of Arts and Sciences, University of Kentucky, Lexington, KY, USA.
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Wooters
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Smith
authors.forename: Marharyta
authors.initials: M
authors.lastname: Pivavarchyk
authors.forename: Kiran B
authors.initials: KB
authors.lastname: Siripurapu
authors.forename: J Michael
authors.initials: JM
authors.lastname: McIntosh
authors.forename: Zhenfa
authors.initials: Z
authors.lastname: Zhang
authors.forename: Peter A
authors.initials: PA
authors.lastname: Crooks
authors.forename: Michael T
authors.initials: MT
authors.lastname: Bardo
authors.forename: Linda P
authors.initials: LP
authors.lastname: Dwoskin
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D020916:Conotoxins / Q000494:pharmacology; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D004361:Drug Tolerance; D066298:In Vitro Techniques; D008297:Male; D009538:Nicotine / Q000008:administration & dosage*; D018733:Nicotinic Antagonists / Q000494:pharmacology*; D010847:Picolines / Q000494:pharmacology*; D011726:Pyridinium Compounds / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000502:physiology*; D012646:Self Administration; D014029:Tobacco Use Disorder / Q000188:drug therapy*
chemical_list: D020916:Conotoxins; C562065:N,N-decane-1,10-diyl-bis-3-picolinium; D018733:Nicotinic Antagonists; D010847:Picolines; D011726:Pyridinium Compounds; D011978:Receptors, Nicotinic; C098872:alpha-conotoxin MII; C559463:alpha6beta2 nicotinic acetylcholine receptor; D009538:Nicotine; D004298:Dopamine