BPiDI: A novel selective α6β2* nicotinic receptor antagonist and preclinical candidate treatment for nicotine abuse

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 C ₁₀ 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 (IC ₅₀ = 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·day ^-1, 10 days) increased more than 100-fold the potency of bPiDI (IC ₅₀ = 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.