Dianicline

Dianicline is a α4β2 nicotinic acetylcholine receptor partial agonist, a class of drugs that includes varenicline and cytisine. Varenicline is efficacious for smoking cessation, while cytisine has not been studied systematically. The efficacy of dianicline has not been previously tested in an adequately powered study.

In a randomized, double-blind, parallel group placebo-controlled trial, 602 generally healthy cigarette smokers were assigned to dianicline (n = 300) or placebo (n = 302) for 7 weeks followed by a 19-week off drug follow-up period.

Exhaled carbon monoxide and cotinine-confirmed continuous abstinence rates for Weeks 4-7 were 24.0% for dianicline versus 20.5% for placebo (odds ratio 1.22; 95% CI, 0.83-1.80; p = .307). For Weeks 4-26, the abstinence rates were 16.7% for dianicline versus 13.9% for placebo (odds ratio 1.24; 95% CI, 0.79-1.93; p = .366). Craving for a cigarettes was reduced by dianicline compared with placebo after 7 weeks (p = .0175). Nicotine withdrawal symptoms measured by the Hughes and Hatsukami Minnesota Withdrawal Scale were lower for dianicline compared with placebo in the first 3 weeks of treatment during which time quit rates were also higher in the dianicline-treated group.

Dianicline did not increase cigarette smoking abstinence rates beyond the initial phase of treatment. However, self-reported craving and nicotine withdrawal symptoms were reduced.

Background and purpose:  Smoking cessation trials with three high‐affinity partial agonists of α4β2 neuronal nicotinic acetylcholine receptors (nAChRs) have demonstrated differences in their clinical efficacy. This work examines the origin of the differences by taking into account brain exposure and pharmacological effects at human α4β2 nAChRs.Experimental approach:  Rat plasma and brain pharmacokinetics were characterized and used to predict human steady‐state plasma and brain concentrations following recommended doses of each of the three compounds. The pharmacological characterization included in vitro affinities at different nAChR subtypes, functional efficacies and potencies at the human α4β2 nAChR, as well as in vivo effects on rat mesolimbic dopamine turn‐over.Key results:  A comparison of predicted human brain concentrations following therapeutic doses demonstrated that varenicline and nicotine, but not dianicline and cytisine, can extensively desensitize and, to a lesser extent, activate α4β2 nAChRs. The limited clinical efficacy of dianicline may be accounted for by a combination of weak functional potency at α4β2 nAChRs and moderate brain penetration, while recommended doses of cytisine, despite its high in vitro potency, are predicted to result in brain concentrations that are insufficient to affect α4β2 nAChRs.Conclusions and implications:  The data provide a plausible explanation for the higher abstinence rate in smoking cessation trials following treatment with varenicline than with the two other α4β2 nAChR partial agonists. In addition, this retrospective analysis demonstrates the usefulness of combining in vitro and in vivo parameters with estimated therapeutic human brain concentrations for translation to clinical efficacy.