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Figure 1. Effects of nicotine, (ꢀ)-cytisine, 1g, 1i, and 1za on dopamine
turnover in rat nucleus accumbens 1 h post-dose. All values are
normalized to the effect of 1.0 mg/kg s.c. nicotine (=100%). Com-
pounds were administered alone (at maximum tolerated doses [filled
bars] of (ꢀ)-(ꢀ)-cytisine, 5.6 mg/kg; 1g, 8 mg/kg; 1i, 10 mg/kg; and 1za,
5 mg/kg) and concurrently with 1 mg/kg s.c. nicotine (open bars).
Mean nicotine increase alone = 177% control; N = 5–10 (all agents
alone: *p < .05 compared to vehicle; all agents with nicotine: +p < .05
compared to nicotine, One-Way ANOVA, post hoc, Dunnettꢀs). Doses
were selected through experimental determination of behavioral
limited ceilings for each agent alone and in combination.
Partial agonists of the a4b2 nAChR hold promise as no-
vel therapeutic aids for smoking cessation. This work
explores carbon analogs of (ꢀ)-cytisine for their poten-
tial as partial agonists of the a4b2 nAChR. Although
some of the derivatives exhibit hints of desirable in vitro
activity, insufficient in vivo efficacy limits their potential
as therapeutic agents. These results encouraged us to ex-
plore modifications to this chemical series that have
yielded compounds with promising in vitro and in vivo
profiles, culminating in the identification of varenicline,
a partial agonist that has been advanced to clinical
trials.42
20. Isolation: (a) Partheil, A. Arch. Pharm. 1894, 232, 161; (b)
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