Varenicline is a partial agonist at α4β2 and a full agonist at α7 neuronal nicotinic receptors

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 alpha 4 beta 2 receptors, and in equilibrium binding assays, it is highly selective for the alpha 4 beta 2 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 alpha 4 beta 2 receptors, with an EC50 of 2.3 +/- 0.3 mu M and an efficacy ( relative to acetylcholine) of 13.4 +/- 0.4%. Varenicline has lower potency and higher efficacy at alpha 3 beta 4 receptors, with an EC50 of 55 +/- 8 mu M and an efficacy of 75 +/- 6%. Varenicline also seems to be a weak partial agonist at alpha 3 beta 2 and alpha 6-containing receptors, with an efficacy < 10%. It is remarkable that varenicline is a potent, full agonist at alpha 7 receptors with an EC50 of 18 +/- 6 mu M 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 alpha 7 receptor. Some combination of these actions may be involved in the mechanism of varenicline as a smoking cessation aid.