title: Pharmacological and molecular studies on the interaction of varenicline with different nicotinic acetylcholine receptor subtypes. Potential mechanism underlying partial agonism at human α4β2 and α3β4 subtypes.
abstract: To determine the structural components underlying differences in affinity, potency, and selectivity of varenicline for several human (h) nicotinic acetylcholine receptors (nAChRs), functional and structural experiments were performed. The Ca2+ influx results established that: (a) varenicline activates (μM range) nAChR subtypes with the following rank sequence: hα7>hα4β4>hα4β2>hα3β4>>>hα1β1γδ; (b) varenicline binds to nAChR subtypes with the following affinity order (nM range): hα4β2~hα4β4>hα3β4>hα7>>>Torpedo α1β1γδ. The molecular docking results indicating that more hydrogen bond interactions are apparent for α4-containing nAChRs in comparison to other nAChRs may explain the observed higher affinity; and that (c) varenicline is a full agonist at hα7 (101%) and hα4β4 (93%), and a partial agonist at hα4β2 (20%) and hα3β4 (45%), relative to (±)-epibatidine. The allosteric sites found at the extracellular domain (EXD) of hα3β4 and hα4β2 nAChRs could explain the partial agonistic activity of varenicline on these nAChR subtypes. Molecular dynamics simulations show that the interaction of varenicline to each allosteric site decreases the capping of Loop C at the hα4β2 nAChR, suggesting that these allosteric interactions limit the initial step in the gating process. In conclusion, we propose that in addition to hα4β2 nAChRs, hα4β4 nAChRs can be considered as potential targets for the clinical activity of varenicline, and that the allosteric interactions at the hα3β4- and hα4β2-EXDs are alternative mechanisms underlying partial agonism at these nAChRs.
authors.affiliation: Department of Medical Education, California Northstate University College of Medicine, Elk Grove, CA, USA. Electronic address: hugo.arias@cnsu.edu.
authors.forename: Hugo R
authors.initials: HR
authors.lastname: Arias
authors.affiliation: Neuroscience Research, Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors.forename: Dominik
authors.initials: D
authors.lastname: Feuerbach
authors.affiliation: Department of Chemistry, Laboratory of Medicinal Chemistry and Neuroengineering, Medical University of Lublin, Lublin, Poland.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Targowska-Duda
authors.affiliation: Department of Synthesis and Chemical Technology of Pharmaceutical Substances with Computer Modeling Lab, Medical University of Lublin, Lublin, Poland.
authors.forename: Agnieszka A
authors.initials: AA
authors.lastname: Kaczor
authors.affiliation: School of Pharmacy, University of Eastern Finland, Kuopio, Finland.
authors.forename: Antti
authors.initials: A
authors.lastname: Poso
authors.affiliation: Department of Chemistry, Laboratory of Medicinal Chemistry and Neuroengineering, Medical University of Lublin, Lublin, Poland.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Jozwiak
mesh_terms: D000494:Allosteric Regulation; D000495:Allosteric Site; D000818:Animals; D001552:Benzazepines / Q000737:chemistry* / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000737:chemistry* / Q000494:pharmacology; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D003412:Cricetulus; D015870:Gene Expression; D057809:HEK293 Cells; D006801:Humans; D006860:Hydrogen Bonding; D062105:Molecular Docking Simulation; D018722:Nicotinic Agonists / Q000737:chemistry* / Q000494:pharmacology; D011485:Protein Binding; D020033:Protein Isoforms / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017433:Protein Structure, Secondary; D011725:Pyridines / Q000737:chemistry* / Q000494:pharmacology; D011810:Quinoxalines / Q000737:chemistry* / Q000494:pharmacology; D011978:Receptors, Nicotinic / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D040681:Structural Homology, Protein; D014101:Torpedo; D019076:Transgenes; D000068580:Varenicline
chemical_list: D001552:Benzazepines; D019086:Bridged Bicyclo Compounds, Heterocyclic; D018722:Nicotinic Agonists; D020033:Protein Isoforms; D011725:Pyridines; D011810:Quinoxalines; D011978:Receptors, Nicotinic; C403530:nicotinic receptor alpha3beta4; C403531:nicotinic receptor alpha4beta2; C082748:epibatidine; D002118:Calcium; D000068580:Varenicline
keywords: Full agonist; Molecular modeling; Nicotinic acetylcholine receptors; Partial agonist; Varenicline