Varenicline is a partial agonist at alpha4beta2 and a full agonist at alpha7 neuronal nicotinic receptors

Mol Pharmacol. 2006 Sep;70(3):801-5. doi: 10.1124/mol.106.025130. Epub 2006 Jun 9.


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 alpha4beta2 receptors, and in equilibrium binding assays, it is highly selective for the alpha4beta2 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 alpha4beta2 receptors, with an EC50 of 2.3 +/- 0.3 microM and an efficacy (relative to acetylcholine) of 13.4 +/- 0.4%. Varenicline has lower potency and higher efficacy at alpha3beta4 receptors, with an EC50 of 55 +/- 8 microM and an efficacy of 75 +/- 6%. Varenicline also seems to be a weak partial agonist at alpha3beta2 and alpha6-containing receptors, with an efficacy <10%. It is remarkable that varenicline is a potent, full agonist at alpha7 receptors with an EC50 of 18 +/- 6 microM 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 alpha7 receptor. Some combination of these actions may be involved in the mechanism of varenicline as a smoking cessation aid.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Benzazepines / chemistry
  • Benzazepines / pharmacology*
  • Neurons / drug effects
  • Neurons / metabolism
  • Nicotinic Agonists / chemistry
  • Nicotinic Agonists / pharmacology*
  • Oocytes / drug effects
  • Quinoxalines / chemistry
  • Quinoxalines / pharmacology*
  • Rats
  • Receptors, Nicotinic / metabolism*
  • Varenicline
  • Xenopus laevis
  • alpha7 Nicotinic Acetylcholine Receptor


  • Benzazepines
  • Chrna7 protein, rat
  • Nicotinic Agonists
  • Quinoxalines
  • Receptors, Nicotinic
  • alpha7 Nicotinic Acetylcholine Receptor
  • nicotinic receptor alpha4beta2
  • Varenicline