Pre-clinical properties of the alpha4beta2 nicotinic acetylcholine receptor partial agonists varenicline, cytisine and dianicline translate to clinical efficacy for nicotine dependence.

BACKGROUND AND PURPOSE: Smoking cessation trials with three high-affinity partial agonists of alpha4beta2 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 alpha4beta2 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 alpha4beta2 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 alpha4beta2 nAChRs. The limited clinical efficacy of dianicline may be accounted for by a combination of weak functional potency at alpha4beta2 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 alpha4beta2 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 alpha4beta2 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.

Pharmacological profile of the alpha4beta2 nicotinic acetylcholine receptor partial agonist varenicline, an effective smoking cessation aid.

The preclinical pharmacology of the alpha4beta2 nicotinic acetylcholine receptor (nAChR) partial agonist varenicline, a novel smoking cessation agent is described. Varenicline binds with subnanomolar affinity only to alpha4beta2 nAChRs and in vitro functional patch clamp studies in HEK cells expressing nAChRs show that varenicline is a partial agonist with 45% of nicotine's maximal efficacy at alpha4beta2 nAChRs. In neurochemical models varenicline has significantly lower (40-60%) efficacy than nicotine in stimulating [(3)H]-dopamine release from rat brain slices in vitro and in increasing dopamine release from rat nucleus accumbens in vivo, while it is more potent than nicotine. In addition, when combined with nicotine, varenicline effectively attenuates the nicotine-induced dopamine release to the level of the effect of varenicline alone, consistent with partial agonism. Finally, varenicline reduces nicotine self-administration in rats and supports lower self-administration break points than nicotine. These data suggest that varenicline can reproduce to some extent the subjective effects of smoking by partially activating alpha4beta2 nAChRs, while preventing full activation of these receptors by nicotine. Based on these findings, varenicline was advanced into clinical development and recently shown to be an effective and safe aid for smoking cessation treatment.

Total synthesis of (+/-)-cytisine via the intramolecular heck cyclization of activated N-alkyl glutarimides.

[reaction:see text] A synthesis of racemic cytisine 1 has been developed utilizing an intramolecular Heck cyclization to prepare the bridged tricyclic intermediate 2. The cyclization employs activated glutarimide-derived ketene aminals 3 (X = P(O)OEt(2) or SO(2)CF(3)) and represents the first use of such intermediates in metal-catalyzed processes.