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4
2 and a Full Agonist at 7 Neuronal Nicotinic Receptors
Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, Florida (K.B.M., C.W.L.); and Organic and Medicinal Chemistry, Research Triangle Institute, Research Triangle Park, North Carolina (F.I.C.)
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, it 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 laevis 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 seems to be a weak partial agonist at 32 and 6-containing receptors, with an efficacy <10%. It is remarkable that 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, whereas 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.
Address correspondence to: Dr. Charles W. Luetje, Department of Molecular and Cellular Pharmacology (R-189), University of Miami Miller School of Medicine, PO Box 016189, Miami, FL 33101. E-mail: cluetje{at}med.miami.edu
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 Z. A. F. Albayati, L. P. Dwoskin, and P. A. Crooks Pharmacokinetics of the Novel Nicotinic Receptor Antagonist N,N'-Dodecane-1,12-diyl-bis-3-picolinium Dibromide in the Rat Drug Metab. Dispos., October 1, 2008; 36(10): 2024 - 2029. [Abstract] [Full Text] [PDF]
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