Varenicline, a widely used and successful smoking cessation agent, acts as a partial agonist at nicotinic acetylcholine receptors. Here we explore the effects of varenicline at human and mouse 5-HT3 receptors. Application of varenicline to human 5-HT3 receptors expressed in Xenopus oocytes reveal it is almost a full agonist (Rmax ~80%) with an EC50 (5.9 µM) ~ 3 fold higher than 5-HT. At mouse 5-HT3 receptors varenicline is a partial agonist (Rmax ~35%) with an EC50 (18 µM) ~20 fold higher than 5-HT. Displacement of the competitive 5-HT3 receptor antagonist [3H]granisetron reveals similar IC50s for varenicline at mouse and human receptors expressed in HEK293 cells, although studies in these cells using a membrane potential sensitive dye show that again varenicline is a ~3 fold or ~20 fold less potent agonist than 5-HT in human and mouse receptors respectively. Thus the data suggest that the efficacy, but not the affinity, of varenicline is greater at human 5-HT3 receptors when compared to mouse. Docking studies provide an explanation for this difference as they suggest distinct orientations of the ligand in the mouse vs human 5-HT3 agonist binding sites. Additional binding selectivity studies in a broad panel of recombinant receptors and enzymes confirmed an interaction with 5-HT3 receptors but revealed no additional interactions of varenicline. Therefore, activation of human 5-HT3 receptors may be responsible for some of the side effects that preclude use of higher doses during varenicline treatment.
- Received June 21, 2011.
- Revision received July 11, 2011.
- Accepted July 11, 2011.
- The American Society for Pharmacology and Experimental Therapeutics