Varenicline Is a Partial Agonist at α4β2 and a Full Agonist at α7 Neuronal Nicotinic Receptors

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Abstract
Varenicline, a new nicotinic ligand based on the structure of cytisine, has recently been approved by the U.S. Food and Drug Administration for use as a smoking cessation aid. Varenicline has been shown to be a partial agonist of α4β2 receptors, and in equilibrium binding assays, it is highly selective for the α4β2 receptor. In this study, we have examined the functional activity of varenicline at a variety of rat neuronal nicotinic receptors expressed in Xenopus laevis oocytes and assayed under two-electrode voltage clamp. We also find that varenicline is a potent, partial agonist at α4β2 receptors, with an EC50 of 2.3 ± 0.3 μM and an efficacy (relative to acetylcholine) of 13.4 ± 0.4%. Varenicline has lower potency and higher efficacy at α3β4 receptors, with an EC50 of 55 ± 8 μM and an efficacy of 75 ± 6%. Varenicline also seems to be a weak partial agonist at α3β2 and α6-containing receptors, with an efficacy 50 of 18 ± 6 μM and an efficacy of 93 ± 7% (relative to acetylcholine). Thus, whereas varenicline is a partial agonist at some heteromeric neuronal nicotinic receptors, it is a full agonist at the homomeric α7 receptor. Some combination of these actions may be involved in the mechanism of varenicline as a smoking cessation aid.

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