Varenicline Is a Partial Agonist at α4β2 and a Full Agonist at α7 Neuronal Nicotinic Receptors

@article{Mihalak2006VareniclineIA,
  title={Varenicline Is a Partial Agonist at $\alpha$4$\beta$2 and a Full Agonist at $\alpha$7 Neuronal Nicotinic Receptors},
  author={Karla B. Mihalak and F. Carroll and C. Luetje},
  journal={Molecular Pharmacology},
  year={2006},
  volume={70},
  pages={801 - 805}
}
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… Expand

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References

SHOWING 1-10 OF 47 REFERENCES
Halogenated cytisine derivatives as agonists at human neuronal nicotinic acetylcholine receptor subtypes
TLDR
It is suggested that cy, N-Me-cy and their halo-isosteres bind to neuronal nACh receptors in a different orientation allowing the halogen atom to interact with a hydrophobic halogen-accepting region within the predominantly hydrophobia agonist-binding pocket of the receptors. Expand
METABOLISM AND DISPOSITION OF VARENICLINE, A SELECTIVE α4β2 ACETYLCHOLINE RECEPTOR PARTIAL AGONIST, IN VIVO AND IN VITRO
The metabolism and disposition of varenicline (7,8,9,10-tetrahydro-6,10-methano-6H-pyrazino[2,3-h][3]benzazepine), a partial agonist of the nicotinic acetylcholine receptor for the treatment ofExpand
Partial agonist properties of cytisine on neuronal nicotinic receptors containing the beta 2 subunit.
TLDR
It is suggested that cytisine is a true partial agonist for beta 2-containing ACh receptors and as such can inhibit the response of these receptors to ACh through a competitive mechanism. Expand
Analogs of α-conotoxin MII are selective for α6-containing nicotinic acetylcholine receptors
Neuronal nicotinic acetylcholine receptors (nAChRs) both mediate direct cholinergic synaptic transmission and modulate synaptic transmission by other neurotransmitters. Novel ligands are needed asExpand
Varenicline: An α4β2 Nicotinic Receptor Partial Agonist for Smoking Cessation
Herein we describe a novel series of compounds from which varenicline (1, 6,7,8,9-tetrahydro-6,10-methano-6H-pyrazino[2,3-h][3]benzazepine) has been identified for smoking cessation. NeuronalExpand
Characterization of the recombinant human neuronal nicotinic acetylcholine receptors α3β2 and α4β2 stably expressed in HEK293 cells
TLDR
The results indicate that stably expressed α3β2 and α4β2 human nAChRs are pharmacologically and functionally distinct. Expand
Nitrogen substitution modifies the activity of cytisine on neuronal nicotinic receptor subtypes.
TLDR
New cytisine derivatives with different substituents on the basic nitrogen bind to both the heteromeric and homomeric subtypes, with higher affinity for brain [3H]epibatidine receptors. Expand
Comparative pharmacology of rat and human α7 nAChR conducted with net charge analysis
TLDR
Dose response curves obtained with these methods indicate that α7 receptors are approximately 10 fold more sensitive to agonist than previously reported, and choline is the least potent agonist for both human and rat α7, with a potency about 10 fold lower than that of ACh. Expand
Effects of Pyridine Ring Substitutions on Affinity, Efficacy, and Subtype Selectivity of Neuronal Nicotinic Receptor Agonist Epibatidine
TLDR
Although these compounds displayed a variety of differences in affinity, efficacy, and potency, with one exception (binding affinity and functional potency at α4β4 receptors) there were no significant correlations among these properties. Expand
Characterization of the recombinant human neuronal nicotinic acetylcholine receptors alpha3beta2 and alpha4beta2 stably expressed in HEK293 cells.
TLDR
The results indicate that stably expressed alpha3beta2 and alpha4beta2 human nAChRs are pharmacologically and functionally distinct and that A3B2 cells are less sensitive to ACh than A4B2.2 cells. Expand
...
1
2
3
4
5
...