Arias, Hugo R, Feuerbach, Dominik, Targowska-Duda, Katarzyna M, Kaczor, Agnieszka A, Poso, Antti and Jozwiak, Krzysztof (2014) Pharmacological and molecular studies on the interaction of varenicline with different nicotinic acetylcholine receptor subtypes. Potential mechanism underlying partial agonism at human 42 and 34 subtypes. Biochimica et Biophysica Acta.

Abstract

In order to determine the structural components underlying differences in affinity, potency, and selectivity of varenicline for several human (h) nicotinic acetylcholine receptors (AChRs), functional and structural experiments were performed. The Ca2+ influx results established that: (a) varenicline activates (EC50s in μM) AChR subtypes with the following rank sequence: hα7 (0.18 ± 0.02) > hα4β4 (0.37 ± 0.08) > hα4β2 (1.30 ± 0.18) > hα3β4 (6.4 ± 1.2) >>> hα1β1γδ (>100); (b) varenicline binds to AChR subtypes with the following affinity order (Kis): hα4β2 (0.090 ± 0.007 nM) ~ hα4β4 (0.121 ± 0.004 nM) > hα3β4 (13 ± 1 nM) > hα7 (77 ± 6 nM) >>> Tα1β1γδ (116 ± 8 μM). The molecular docking results indicating that more hydrogen bond interactions are apparent for 4-containing AChRs in comparison to other AChRs 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 h34 and h42 AChRs could explain the partial agonistic activity of varenicline on these AChR subtypes. Molecular dynamics simulations show that the interaction of varenicline to each allosteric site decreases the capping of Loop C at the hα4β2 AChR, suggesting that these allosteric interactions limit the initial step in the gating process. In conclusion, we propose that in addition to hα4β2 AChRs, hα4β4 AChRs can be considered as potential targets for the clinical activity of varenicline, and that the allosteric interactions at the h34- and h42-EXDs are alternative mechanisms underlying partial agonism at these AChRs.

Item Type:	Article
Date Deposited:	26 Apr 2016 23:45
Last Modified:	26 Apr 2016 23:45
URI:	https://oak.novartis.com/id/eprint/22713