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

Abstract

BACKGROUND AND PURPOSENicotinic acetylcholine receptors (nAChRs) containing a6b2 subunits expressed by dopamine neurons regulate nicotine-evoked dopamine release. Previous results show that the a6b2* nAChR antagonist, N,NЈ-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 APPROACHThe C10 analogue of bPiDDB, N, , was evaluated preclinically for nAChR antagonist activity. KEY RESULTSbPiDI inhibits nicotine-evoked [ 3 H]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 mM) and the a6b2* nAChR antagonist a-conotoxin MII (1 nM) produced inhibition not different from either antagonist alone, indicating that bPiDI acts at a6b2* 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 mmol·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 IMPLICATIONSThese results are consistent with the hypothesis that a6b2* nAChR antagonists have potential for development as pharmacotherapies for tobacco smoking cessation.Abbreviations bPIDDB, N, bPiDI, N,picolinium diiodide; DHbE, dihydro-b-erythroidine; FR5, fixed ratio 5; NAcc, nucleus accumbens; nAChR, nicotinic acetylcholine receptor; s.c., subcutaneous; TO180, 180 min timeout; TO20, 20 min timeout; VTA, ventral tegmental area; a-CtxMII, a-conotoxin MII BJP British Journal of Pharmacology DOI:10.1111DOI:10. /j.1476DOI:10. -5381.2011 346 British Journal of Pharmacology (2011) IntroductionDrugs of abuse activate the dopaminergic reward circuitry, leading to dopamine release in nucleus accumbens (NAcc) and striatum, which is associated with primary reward and habit formation respectively (Di Chiara et al., 2004;Koob and Volkow, 2010). The transition from reward seeking to compulsive behaviour associated with drug abuse appears to result from a shift from NAcc to striatal control (Koob and Volkow, 2010). Nicotine activates nicotinic acetylcholine receptors (nAChRs; receptor nomenclature follows Alexander et al., 2009) that modulate dopamine release. Identifying nAChRs regulating dopamine release is important because dopami...

Positional Scanning Mutagenesis of α-Conotoxin PeIA Identifies Critical Residues That Confer Potency and Selectivity for α6/α3β2β3 and α3β2 Nicotinic Acetylcholine Receptors

“…This situation has now been remedied with the availability of PeIA(A7V,S9H,V10A,N11R,E14A), and this new analog may be particularly useful for differentiating the role of ␣6␤2* from that of ␣3␤2* nAChRs in the nigrostriatal system. Additionally, converging evidence from multiple studies suggests that drugs that target ␣6␤2* may be useful in the pharmacotherapy of Parkinson disease and nicotine dependence (45,46). However, compounds that target ␣6␤2* would need to be devoid of activity on the ␣3␤2* subtype to avoid unwanted cardiovascular and enteric side effects.…”

Nicotinic Receptor Antagonists as Treatments for Nicotine Abuse

“…It should be noted that when administered peripherally, several bis-quaternary ammonium antagonists, including bPiDDB, specifically decreased nicotine self-administration and reinstatement of nicotine seeking in rats, providing proof of concept of this representative class of drug as a new pharmacotherapy for nicotine addiction. Additional behavioral studies in the rat have been carried out on other structurally related N,N ′-alkane-diyl-bis-3-picoliniums (Dwoskin et al, 2008; Wooters et al, 2011). …”

α6β2 nicotinic acetylcholine receptors influence locomotor activity and ethanol consumption

“…Until recently, no drugs that cross the blood brain barrier and specifically target α6-containing nAChRs have been available. Recently, a novel α6β2 nAChR antagonist, N,N-decane-1,10-diyl-bis-3-picolinium diiodide (bPiDI), has been described (Wooters et al, 2011). These receptors are the major subtype of nAChRs found in the nucleus accumbens which is a key brain region in modulating drug use (Quik, Perez, & Grady, 2011).…”