title: Varenicline is a potent agonist of the human 5-hydroxytryptamine3 receptor.
abstract: 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-Hydroxytryptamine(3) (5-HT(3)) receptors. Application of varenicline to human 5-HT(3) receptors expressed in Xenopus laevis oocytes reveal it is almost a full agonist (R(max) = 80%) with an EC(50) (5.9 μM) 3-fold higher than 5-HT. At mouse 5-HT(3) receptors varenicline is a partial agonist (R(max) = 35%) with an EC(50) (18 μM) 20-fold higher than 5-HT. Displacement of the competitive 5-HT(3) receptor antagonist [(3)H]granisetron reveals similar IC(50) values for varenicline at mouse and human receptors expressed in human embryonic kidney 293 cells, although studies in these cells using a membrane potential-sensitive dye show that again varenicline is a 4- or 35-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-HT(3) receptors compared with mouse. Docking studies provide a possible explanation for this difference, because they suggest distinct orientations of the ligand in the mouse versus human 5-HT(3) agonist binding sites. Additional binding selectivity studies in a broad panel of recombinant receptors and enzymes confirmed an interaction with 5-HT(3) receptors but revealed no additional interactions of varenicline. Therefore, activation of human 5-HT(3) receptors may be responsible for some of the side effects that preclude use of higher doses during varenicline treatment.
authors.affiliation: Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge CB2 1QW, United Kingdom. sl120@cam.ac.uk
authors.forename: S C R
authors.initials: SC
authors.lastname: Lummis
authors.forename: A J
authors.initials: AJ
authors.lastname: Thompson
authors.forename: M
authors.initials: M
authors.lastname: Bencherif
authors.forename: H A
authors.initials: HA
authors.lastname: Lester
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001552:Benzazepines / Q000494:pharmacology*; D001665:Binding Sites / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D055724:Electrophysiological Phenomena; D017829:Granisetron / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D018722:Nicotinic Agonists / Q000494:pharmacology*; D009865:Oocytes / Q000378:metabolism; D018408:Patch-Clamp Techniques; D011810:Quinoxalines / Q000494:pharmacology*; D011869:Radioligand Assay; D044406:Receptors, Serotonin, 5-HT3 / Q000096:biosynthesis / Q000235:genetics; D058827:Serotonin 5-HT3 Receptor Agonists; D013045:Species Specificity; D000068580:Varenicline; D014982:Xenopus laevis
chemical_list: D001552:Benzazepines; D017829:Granisetron; D018722:Nicotinic Agonists; D011810:Quinoxalines; D044406:Receptors, Serotonin, 5-HT3; D058827:Serotonin 5-HT3 Receptor Agonists; D000068580:Varenicline