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

Hugo R. Arias, Dominik Feuerbach, Katarzyna Targowska-Duda, Agnieszka A. Kaczor, Antti Poso, Krzysztof Jozwiak

Research output: Contribution to journalArticle

13 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)731-741
Number of pages11
JournalBiochimica et Biophysica Acta - Biomembranes
Volume1848
Issue number2
DOIs
StatePublished - 1 Jan 2015
Externally publishedYes

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Nicotinic Receptors
Pharmacology
Allosteric Site
epibatidine
Torpedo
Molecular Dynamics Simulation
Varenicline
Molecular dynamics
Hydrogen
Hydrogen bonds
Computer simulation

Keywords

  • Full agonist
  • Molecular modeling
  • Nicotinic acetylcholine receptors
  • Partial agonist
  • Varenicline

Cite this

@article{abf79a21c40445a0b497b307092dbc56,
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.",
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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. / Arias, Hugo R.; Feuerbach, Dominik; Targowska-Duda, Katarzyna; Kaczor, Agnieszka A.; Poso, Antti; Jozwiak, Krzysztof.

In: Biochimica et Biophysica Acta - Biomembranes, Vol. 1848, No. 2, 01.01.2015, p. 731-741.

Research output: Contribution to journalArticle

TY - JOUR

T1 - 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

AU - Arias, Hugo R.

AU - Feuerbach, Dominik

AU - Targowska-Duda, Katarzyna

AU - Kaczor, Agnieszka A.

AU - Poso, Antti

AU - Jozwiak, Krzysztof

PY - 2015/1/1

Y1 - 2015/1/1

N2 - 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.

AB - 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.

KW - Full agonist

KW - Molecular modeling

KW - Nicotinic acetylcholine receptors

KW - Partial agonist

KW - Varenicline

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