Pre‐clinical properties of the α4β2 nicotinic acetylcholine receptor partial agonists varenicline, cytisine and dianicline translate to clinical efficacy for nicotine dependence

Abstract

Background and purpose:Smoking cessation trials with three high-affinity partial agonists of a4b2 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 a4b2 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 a4b2 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 a4b2 nAChRs. The limited clinical efficacy of dianicline may be accounted for by a combination of weak functional potency at a4b2 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 a4b2 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 a4b2 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.

A Single Administration of Low-Dose Varenicline Saturates α4β2* Nicotinic Acetylcholine Receptors in the Human Brain

“…This concentration of varenicline is lower than the reported therapeutic window (32-131 nM) in mediating smoking cessation using standard dosing regimens (Rollema et al, 2010). Indeed, it is interesting to note that the 32-131 nM concentrations of varenicline desensitize human a4b2* nAChRs to repeated administrations of acetylcholine in oocyte electrophysiological studies (IC 50 ¼ 0.07 nM) (Rollema et al, 2010). A single low dose of varenicline leads to a plasma level below the window that induces the desensitization response and the latter may be required to mediate a behavioral effect.…”

“…Our data show that single low-dose (0.5 mg) administration produces a 3-5 nM (1.1-1.7 ng/ml) concentration of varenicline in human blood plasma, which lead to complete saturation of a4b2* nAChRs in the human brain. This concentration of varenicline is lower than the reported therapeutic window (32-131 nM) in mediating smoking cessation using standard dosing regimens (Rollema et al, 2010). Indeed, it is interesting to note that the 32-131 nM concentrations of varenicline desensitize human a4b2* nAChRs to repeated administrations of acetylcholine in oocyte electrophysiological studies (IC 50 ¼ 0.07 nM) (Rollema et al, 2010).…”

“…Based on in-vivo measurements of free drug exposures in the brain, the extracellular brain concentration is expected to be nearly identical to the plasma concentration (Rollema et al, 2010). Thus, our upper limit is relevant to the true value of K V .…”

“…It has previously been demonstrated that withdrawal symptoms do not respond to a single dose of varenicline but require chronic treatment. Thus, the current paper aims to determine whether in fact low-dose varenicline at the 0.5 mg dose actually binds to a4b2* nAChRs in humans and whether the effect is maximal, ie, by virtue of nearly full saturation, as predicted from preclinical studies (Rollema et al, 2010). Our findings demonstrate that even near-saturation of the receptors does not alleviate withdrawal symptoms.…”

Functional Characterization of AT-1001, an α3β4 Nicotinic Acetylcholine Receptor Ligand, at Human α3β4 and α4β2 nAChR

“…Varenicline mainly inhibits the functional activity of its main target, the α4β2 nAChR, while activating only a minor fraction, 27 while desensitization of a small fraction of an off-target receptor, the α3β4* nAChR, may contribute to its effect. 28 AT-1001 appears to represent an intriguing "opposite" mechanism, in that its main effect is inhibition/desensitization of the α3β4* nAChR, with a possible contribution by inhibition of a minor fraction of α4β2* nAChR.…”