bPiDI: a novel selective α6β2 nicotinic receptor antagonist and preclinical candidate treatment for nicotine abuse

• Published in: British journal of pharmacology Vol. 163; no. 2; pp. 346 - 357
• Main Authors: Wooters, Thomas E, Smith, Andrew M, Pivavarchyk, Marharyta, Siripurapu, Kiran B, McIntosh, J Michael, Zhang, Zhenfa, Crooks, Peter A, Bardo, Michael T, Dwoskin, Linda P
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.05.2011; Nature Publishing Group
• Subjects: Allosteric Regulation; Animals; Biological and medical sciences; Conotoxins - pharmacology; Corpus Striatum - drug effects; Corpus Striatum - metabolism; dopamine; Dopamine - metabolism; Drug Tolerance; In Vitro Techniques; Male; Medical sciences; nicotine; Nicotine - administration & dosage; Nicotinic Antagonists - pharmacology; nicotinic receptor antagonist; Pharmacology. Drug treatments; Picolines - pharmacology; Pyridinium Compounds - pharmacology; rat; Rats; Rats, Sprague-Dawley; Receptors, Nicotinic - physiology; Research Papers; Self Administration; tobacco smoking; Tobacco Use Disorder - drug therapy; Tobacco, tobacco smoking; Toxicology; α6β2; Dopamine; Rat; Rodentia; Tobacco smoking; Preclinical trial; Self administration; α6β2; Catecholamine; Alkaloid; Cholinergic receptor; Vertebrata; Mammalia; Treatment; self-administration; Animal; Neurotransmitter; nicotinic receptor antagonist; Antagonist; Nicotinic receptor; Nicotine
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/j.1476-5381.2011.01220.x

BACKGROUND AND PURPOSE 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. EXPERIMENTAL APPROACH The C10 analogue of bPiDDB, N,N‐decane‐1,10‐diyl‐bis‐3‐picolinium diiodide (bPiDI), was evaluated preclinically for nAChR antagonist activity. KEY RESULTS bPiDI inhibits nicotine‐evoked [3H]dopamine overflow (IC50 = 150 nM, Imax = 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·day−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 AND IMPLICATIONS These results are consistent with the hypothesis that α6β2* nAChR antagonists have potential for development as pharmacotherapies for tobacco smoking cessation.