Varenicline is a partial agonist at α4β2 and a full agonist at α7 neuronal nicotinic receptors

Karla B. Mihalak, F. Ivy Carroll, Charles W Luetje

Research output: Contribution to journalArticle

407 Citations (Scopus)

Abstract

Varenicline, a new nicotinic ligand based on the structure of cytisine, has recently been approved by the U.S. Food and Drug Administration for use as a smoking cessation aid. Varenicline has been shown to be a partial agonist of α4β2 receptors, and in equilibrium binding assays, it is highly selective for the α4β2 receptor. In this study, we have examined the functional activity of varenicline at a variety of rat neuronal nicotinic receptors expressed in Xenopus laevis oocytes and assayed under two-electrode voltage clamp. We also find that varenicline is a potent, partial agonist at α4β2 receptors, with an EC50 of 2.3 ± 0.3 μM and an efficacy (relative to acetylcholine) of 13.4 ± 0.4%. Varenicline has lower potency and higher efficacy at α3β4 receptors, with an EC 50 of 55 ± 8 μM and an efficacy of 75 ± 6%. Varenicline also seems to be a weak partial agonist at α3β2 and α6-containing receptors, with an efficacy ≤10%. It is remarkable that varenicline is a potent, full agonist at α7 receptors with an EC 50 of 18 ± 6 μM and an efficacy of 93 ± 7% (relative to acetylcholine). Thus, whereas varenicline is a partial agonist at some heteromeric neuronal nicotinic receptors, it is a full agonist at the homomeric α7 receptor. Some combination of these actions may be involved in the mechanism of varenicline as a smoking cessation aid.

Original languageEnglish
Pages (from-to)801-805
Number of pages5
JournalMolecular Pharmacology
Volume70
Issue number3
DOIs
StatePublished - Aug 28 2006

Fingerprint

Nicotinic Receptors
Smoking Cessation
Acetylcholine
Varenicline
Xenopus laevis
United States Food and Drug Administration
Oocytes
Electrodes
Ligands

ASJC Scopus subject areas

  • Pharmacology

Cite this

Varenicline is a partial agonist at α4β2 and a full agonist at α7 neuronal nicotinic receptors. / Mihalak, Karla B.; Carroll, F. Ivy; Luetje, Charles W.

In: Molecular Pharmacology, Vol. 70, No. 3, 28.08.2006, p. 801-805.

Research output: Contribution to journalArticle

Mihalak, Karla B. ; Carroll, F. Ivy ; Luetje, Charles W. / Varenicline is a partial agonist at α4β2 and a full agonist at α7 neuronal nicotinic receptors. In: Molecular Pharmacology. 2006 ; Vol. 70, No. 3. pp. 801-805.
@article{8d5bfa5ad4e44831bc0a8e0223631c95,
title = "Varenicline is a partial agonist at α4β2 and a full agonist at α7 neuronal nicotinic receptors",
abstract = "Varenicline, a new nicotinic ligand based on the structure of cytisine, has recently been approved by the U.S. Food and Drug Administration for use as a smoking cessation aid. Varenicline has been shown to be a partial agonist of α4β2 receptors, and in equilibrium binding assays, it is highly selective for the α4β2 receptor. In this study, we have examined the functional activity of varenicline at a variety of rat neuronal nicotinic receptors expressed in Xenopus laevis oocytes and assayed under two-electrode voltage clamp. We also find that varenicline is a potent, partial agonist at α4β2 receptors, with an EC50 of 2.3 ± 0.3 μM and an efficacy (relative to acetylcholine) of 13.4 ± 0.4{\%}. Varenicline has lower potency and higher efficacy at α3β4 receptors, with an EC 50 of 55 ± 8 μM and an efficacy of 75 ± 6{\%}. Varenicline also seems to be a weak partial agonist at α3β2 and α6-containing receptors, with an efficacy ≤10{\%}. It is remarkable that varenicline is a potent, full agonist at α7 receptors with an EC 50 of 18 ± 6 μM and an efficacy of 93 ± 7{\%} (relative to acetylcholine). Thus, whereas varenicline is a partial agonist at some heteromeric neuronal nicotinic receptors, it is a full agonist at the homomeric α7 receptor. Some combination of these actions may be involved in the mechanism of varenicline as a smoking cessation aid.",
author = "Mihalak, {Karla B.} and Carroll, {F. Ivy} and Luetje, {Charles W}",
year = "2006",
month = "8",
day = "28",
doi = "10.1124/mol.106.025130",
language = "English",
volume = "70",
pages = "801--805",
journal = "Molecular Pharmacology",
issn = "0026-895X",
publisher = "American Society for Pharmacology and Experimental Therapeutics",
number = "3",

}

TY - JOUR

T1 - Varenicline is a partial agonist at α4β2 and a full agonist at α7 neuronal nicotinic receptors

AU - Mihalak, Karla B.

AU - Carroll, F. Ivy

AU - Luetje, Charles W

PY - 2006/8/28

Y1 - 2006/8/28

N2 - Varenicline, a new nicotinic ligand based on the structure of cytisine, has recently been approved by the U.S. Food and Drug Administration for use as a smoking cessation aid. Varenicline has been shown to be a partial agonist of α4β2 receptors, and in equilibrium binding assays, it is highly selective for the α4β2 receptor. In this study, we have examined the functional activity of varenicline at a variety of rat neuronal nicotinic receptors expressed in Xenopus laevis oocytes and assayed under two-electrode voltage clamp. We also find that varenicline is a potent, partial agonist at α4β2 receptors, with an EC50 of 2.3 ± 0.3 μM and an efficacy (relative to acetylcholine) of 13.4 ± 0.4%. Varenicline has lower potency and higher efficacy at α3β4 receptors, with an EC 50 of 55 ± 8 μM and an efficacy of 75 ± 6%. Varenicline also seems to be a weak partial agonist at α3β2 and α6-containing receptors, with an efficacy ≤10%. It is remarkable that varenicline is a potent, full agonist at α7 receptors with an EC 50 of 18 ± 6 μM and an efficacy of 93 ± 7% (relative to acetylcholine). Thus, whereas varenicline is a partial agonist at some heteromeric neuronal nicotinic receptors, it is a full agonist at the homomeric α7 receptor. Some combination of these actions may be involved in the mechanism of varenicline as a smoking cessation aid.

AB - Varenicline, a new nicotinic ligand based on the structure of cytisine, has recently been approved by the U.S. Food and Drug Administration for use as a smoking cessation aid. Varenicline has been shown to be a partial agonist of α4β2 receptors, and in equilibrium binding assays, it is highly selective for the α4β2 receptor. In this study, we have examined the functional activity of varenicline at a variety of rat neuronal nicotinic receptors expressed in Xenopus laevis oocytes and assayed under two-electrode voltage clamp. We also find that varenicline is a potent, partial agonist at α4β2 receptors, with an EC50 of 2.3 ± 0.3 μM and an efficacy (relative to acetylcholine) of 13.4 ± 0.4%. Varenicline has lower potency and higher efficacy at α3β4 receptors, with an EC 50 of 55 ± 8 μM and an efficacy of 75 ± 6%. Varenicline also seems to be a weak partial agonist at α3β2 and α6-containing receptors, with an efficacy ≤10%. It is remarkable that varenicline is a potent, full agonist at α7 receptors with an EC 50 of 18 ± 6 μM and an efficacy of 93 ± 7% (relative to acetylcholine). Thus, whereas varenicline is a partial agonist at some heteromeric neuronal nicotinic receptors, it is a full agonist at the homomeric α7 receptor. Some combination of these actions may be involved in the mechanism of varenicline as a smoking cessation aid.

UR - http://www.scopus.com/inward/record.url?scp=33747598710&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33747598710&partnerID=8YFLogxK

U2 - 10.1124/mol.106.025130

DO - 10.1124/mol.106.025130

M3 - Article

VL - 70

SP - 801

EP - 805

JO - Molecular Pharmacology

JF - Molecular Pharmacology

SN - 0026-895X

IS - 3

ER -