Cited by 102Nicotinic Acetylcholine Receptors StudyNeuroscience and Neuropharmacology ResearchSmoking Behavior and Cessation

Structural differences determine the relative selectivity of nicotinic compounds for native α4β2*-, α6β2*-, α3β4*- and α7-nicotine acetylcholine receptors

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Grady, Sharon R., Drenan, Ryan M., Breining, Scott R., Yohannes, Daniel, Wageman, Charles R., Fedorov, Nikolai B., McKinney, Sheri, Whiteaker, Paul +3 more·2010·Neuropharmacology

Abstract

Mammalian brain expresses multiple nicotinic acetylcholine receptor (nAChR) subtypes that differ in subunit composition, sites of expression and pharmacological and functional properties. Among known subtypes of receptors, alpha 4 beta 2* and alpha 6 beta 2*-nAChR have the highest affinity for nicotine (where * indicates possibility of other subunits). The alpha 4 beta 2*-nAChRs are widely distributed, while alpha 6 beta 2*-nAChR are restricted to a few regions. Both subtypes modulate release of dopamine from the dopaminergic neurons of the mesoaccumbens pathway thought to be essential for reward and addiction. alpha 4 beta 2*-nAChR also modulate GABA release in these areas. Identification of selective compounds would facilitate study of nAChR subtypes. An improved understanding of the role of nAChR subtypes may help in developing more effective smoking cessation aids with fewer side effects than current therapeutics. We have screened a series of nicotinic compounds that vary in the distance between the pyridine and the cationic center, in steric bulk, and in flexibility of the molecule. These compounds were screened using membrane binding and synaptosomal function assays, or recordings from GH4C1 cells expressing h alpha 7, to determine affinity, potency and efficacy at four subtypes of nAChRs found in brain, alpha 4 beta 2*, alpha 6 beta 2*, alpha 7 and alpha 3 beta 4*. In addition, physiological assays in gain-of-function mutant mice were used to assess in vivo activity at alpha 4 beta 2* and alpha 6 beta 2*-nAChRs. This approach has identified several compounds with agonist or partial agonist activity that display improved selectivity for alpha 6 beta 2*-nAChR.

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Crossref · 10.1016/j.neuropharm.2010.01.013

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Authors
Grady, S. R., Drenan, R. M., Breining, S. R., Yohannes, D., Wageman, C. R., Fedorov, N. B., McKinney, S., Whiteaker, P., Bencherif, M., Lester, H. A., & Marks, M. J.
Affiliations
  • University of Colorado Boulder (US)
  • California Institute of Technology (US)
Corresponding author
Grady, Sharon R.
Venue
Neuropharmacology
Publisher
Elsevier BV
Published
2010-06
Volume
58
Issue
7
Pages
1054-1066
ISSN
0028-3908 (ISSN-L)
OpenAlex
W2068493106
Cited by
98
References
50
Citations by year
2025: 1 · 2023: 4 · 2022: 3 · 2021: 2 · 2020: 4 · 2019: 4 · 2018: 9 · 2017: 6 · 2016: 10 · 2015: 9 · 2014: 15 · 2013: 10 · 2012: 12
FWCI
4.43
Type
journal article
Language
en
Open access
Locations
  • Neuropharmacology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • CaltechAUTHORS (California Institute of Technology) (submittedVersion)
Funders
National Institute on Drug Abuse (U19DA019375, DA 015663, R01DA017279, P30DA015663)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Health Sciences › Medicine › Physiology › Smoking Behavior and Cessation
Keywords
nicotinic acetylcholine receptors, receptor subtype selectivity, alpha4beta2 receptor, alpha7 nicotinic acetylcholine receptor, nicotinic agonists, partial agonists, dopamine release, GABA release, smoking cessation aids, steric bulk, receptor binding affinity
MeSH terms
Animals, Body Temperature, Brain, Cell Line, Drug Evaluation, Preclinical, Elasticity, Mice, Transgenic, Protein Conformation, Pyridines, Receptors, Nicotinic, Synaptosomes, Molecular Structure, Mice, Knockout, Nicotinic Agonists, Nicotinic Antagonists, Mice, Gene Knock-In Techniques, alpha7 Nicotinic Acetylcholine Receptor

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