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Received for publication April 4, 2006.
Revised June 3, 2006.
Accepted for publication June 9, 2006.
4
2 and a full agonist at 7 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 
4
2 receptors and in equilibrium binding assays varenicline is highly selective for the 42 receptor. In this study, we have examined the functional activity of varenicline at a variety of rat neuronal nicotinic receptors expressed in Xenopus oocytes and assayed under two electrode voltage clamp. We also find that varenicline is a potent, partial agonist at 42 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 34 receptors with an EC50 of 55 ± 8 µM and an efficacy of 75 ± 6%. Varenicline also appears to be a weak partial agonist at 32 and 6-containing receptors, with an efficacy <10%. Remarkably, varenicline is a potent, full agonist at 7 receptors with an EC50 of 18 ± 6 µM and an efficacy of 93 ± 7% (relative to acetylcholine). Thus, while varenicline is a partial agonist at some heteromeric neuronal nicotinic receptors, it is a full agonist at the homomeric 7 receptor. Some combination of these actions may be involved in the mechanism of varenicline as a smoking cessation aid.
Key words:
Nicotinic cholinergic, Func. analysis receptor/ion channel mutants
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