Nicotinic receptor antagonists as treatments for nicotine abuse

Abstract

Despite the proven efficacy of current pharmacotherapies for tobacco dependence, relapse rates continue to be high, indicating that novel medications are needed. Currently, several smoking cessation agents are available, including varenicline (Chantix®), bupropion (Zyban®), and cytisine (Tabex®). Varenicline and cytisine are partial agonists at the α4β2* nicotinic acetylcholine receptor (nAChR). Bupropion is an antidepressant but is also an antagonist at α3β2* ganglionic nAChRs. The rewarding effects of nicotine are mediated, in part, by nicotine-evoked dopamine (DA) release leading to sensitization, which is associated with repeated nicotine administration and nicotine addiction. Receptor antagonists that selectivity target central nAChR subtypes mediating nicotine-evoked DA release should have efficacy as tobacco use cessation agents with the therapeutic advantage of a limited side-effect profile. While α-conotoxin MII (α-CtxMII)-insensitive nAChRs (e.g., α4β2*) contribute to nicotine-evoked DA release, these nAChRs are widely distributed in the brain, and inhibition of these receptors may lead to nonselective and untoward effects. In contrast, α-CtxMII-sensitive nAChRs mediating nicotine-evoked DA release offer an advantage as targets for smoking cessation, due to their more restricted localization primarily to dopaminergic neurons. Small drug-like molecules that are selective antagonists at α-CtxMII-sensitive nAChR subtypes that contain α6 and β2 subunits have now been identified. Early research identified a variety of quaternary ammonium analogs that were potent and selective antagonists at nAChRs mediating nicotine-evoked DA release. More recent data have shown that novel, nonquaternary bis-1,2,5,6-tetrahydropyridine analogs potently inhibit (IC50<1nM) nicotine-evoked DA release in vitro by acting as antagonists at α-CtxMII-sensitive nAChR subtypes; these compounds also decrease NIC self-administration in rats.

Keywords: Nicotine analogs; Nicotine dependence; Nicotinic receptor antagonists; Relapse; Smoking cessation.

Figure 13.1

Chemical structures of the N-n-alkyl-substituted analogs of S-(−)-nicotine, NONI (S-(−)-N-n-octylnicotinium iodide), NDNI (S-(−)-N-n-decylnicotinium bromide, and NDDNI (S-(−)-N-n-dodecylnicotinium iodide. NONI exhibited an IC₅₀ of 0.62 µM at α6-containing nAChRs.

Figure 13.2

Chemical structures of the bis-quaternary ammonium compounds bNDI (S-(−)-N,N-decane-1,10-diyl-bis-nicotinium diiodide), bQDDB (N,N-dodecane-1,12-diyl-bis-quinolinium dibromide), and bPiDDB (N,N-dodecane-1,12-diyl-bis-3-picolinium dibromide). bPiDDB exhibited an IC₅₀ of 5 µM at α6-containing nAChRs.

Figure 13.3

General chemical structures of conformationally restricted analogs of bPiDDB that incorporate 1,2-, 1,3-, and 1,4-dialkylphenyl linkers between the two quaternary ammonium headgroups. This structural change generally led to a decrease in the inhibition of nicotine-evoked DA release.

Figure 13.4

Concentration of ¹⁴C-bPiDDB in the plasma and brain after 1 and 3 mg/kg administration of ¹⁴C-bpiDDB in the Sprague–Dawley rat.

Figure 13.5

Acute bPiDDB (1 and 3 mg/kg) decreases NIC self-administration: bPiDDB (0.3–3 mg/kg, s.c, 15 min pretreatment) decreased the number of nicotine infusions (0.03 mg/kg/infusion) earned (active lever).

Figure 13.6

Synthetic scheme for the synthesis of tris-3-picolinium analogs.

Figure 13.7

Structures of the two tris-quaternary ammonium scaffolds A (1,3,5-tri-{5-[1-(ammonium)-pent-1-ynyl}benzene) and B (1,3,5-tri-{5-[1-(ammonium)-pentyl}benzene); TRIS-1 scaffold A, NR₃ = 3-picolinium; TRIS-2 scaffold A, NR₃ = 2-picolinium; TRIS-3 scaffold B, NR₃ = 3-picolinium.

Figure 13.8

Synthetic scheme for the synthesis of tetrakis-3-picolinium and tetrakis-isoquinolinium analogs.

Figure 13.9

Structures of the two tetrakis-quaternary ammonium scaffolds A (1,2,4,5-tetrakis-{5-[1-(ammonium)-pent-1-ynyl}benzene) and B (1,2,4,5-tetrakis-{5-[1-(ammonium)-pentyl}benzene); TETRAKIS-1 scaffold A, NR₃ = 3-benzylpyridinium; TETRAKIS-2 scaffold A, NR₃ = quinolinium; TETRAKIS-3 scaffold B, NR₃ = 3-(3-hydroxypropyl)-pyridinium.

Figure 13.10

Structure of BTMPS and structurally related analogs; IC₅₀ and I_max values of TMP and mecamylamine analogs in the nicotine-evoked dopamine release assay are also provided.

Figure 13.11

Structures, IC₅₀ and I_max values of the three lead analogs, (±)-1-[12-(3-methyl-1,2,5,6-tetrahydropyridin-1-yl)dodecyl]-3,5-dimethyl-1,2,5,6-tetrahydropyridine (bis-THPI), 1,12-bis(3-methyl-1,2,5,6-tetrahydropyridinyl)dodecane (bis-THP3), and 1,10-bis(3-methyl-1,2,5,6-tetrahydropyridinyl)decane (bis-THP4).

Figure 13.12

Top: Concentration-dependent inhibition of NIC-evoked [³H]-DA release by bis-THP3 (bPiDDB) and bis-THP1 in rat striatum in vitro (Dwoskin, Pivavarchyk, et al., 2009; Smith et al., 2010). (One-way ANOVAs: bis-THP3, F8, 16 = 33.9, p<0.05; bis-THP1, F7, 27=10.7, p<0.01; n = 9 and 8, respectively.) Center: Inhibition of NIC-evoked [³H]-DA release by maximally effective concentrations of bis-THP3 is not additive with a maximally effective α-CtxMII concentration in vitro (one-way ANOVAs:THP3, F4,15 = 82.1, p<0.001 n = 4. *p<0.05 compared to control; #p<0.05 compared to α-CtxMII + bis-THP3). Bottom: bis-THP3 and bis-THP1 (s.c.) decrease NIC self-administration (i.v.) at doses that do not alter food-maintained responding; n = 4–8 per group. *p<0.05, **p<0.01 compared to control.