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Structural differences determine the relative selectivity of nicotinic compounds for native α4β2*-, α6β2*-, α3β4*- and α7-nicotine acetylcholine receptors
Open accessAbstract
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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“a non-nicotine pharmaceutical currently FDA approved for the treatment of smoking cessation, varenicline, acts as a partial agonist at α6β2* nAChRs (Grady et al. 2010; Bordia et al. 2012).”
From Nicotine Withdrawal (2015) · cites this paper as Grady et al. 2010
In the citing paper
“subsequent work showed that varenicline had a significant effect at ␣7 nAChRs, ␣34* nAChRs, and 5-hydroxytryptamine type 3 receptors”
From Varenicline Is a Potent Partial Agonist at α6β2* Nicotinic Acetylcholine Receptors in Rat and Monkey Striatum (2012) · cites this paper as Grady et al., 2010
In the citing paper
“Work with ␣-CtxMII to delineate the contribution of the ␣62* and ␣42* nAChRs to varenicline-evoked release showed that varenicline was a partial agonist at both subtypes, in agreement with others (Grady et al., 2010).”
From Varenicline Is a Potent Partial Agonist at α6β2* Nicotinic Acetylcholine Receptors in Rat and Monkey Striatum (2012) · cites this paper as Grady et al., 2010
In the citing paper
“Although ␣62* nAChRs play an important role in addiction, the effect of varenicline on ␣62* nAChR-mediated function in CNS dopaminergic systems is currently unclear”
From Varenicline Is a Potent Partial Agonist at α6β2* Nicotinic Acetylcholine Receptors in Rat and Monkey Striatum (2012) · cites this paper as Grady et al., 2010
In the citing paper
“It is noteworthy that the binding affinity of varenicline for ␣62* nAChRs was very similar to that of ␣42* nAChRs, in agreement with Grady et al. (2010).”
From Varenicline Is a Potent Partial Agonist at α6β2* Nicotinic Acetylcholine Receptors in Rat and Monkey Striatum (2012) · cites this paper as Grady et al., 2010
In the citing paper
“Thus the mode of interaction of varenicline at ␣62* nAChRs is similar to that at ␣42* nAChRs, as shown here and reported by others (Grady et al., 2010).”
From Varenicline Is a Potent Partial Agonist at α6β2* Nicotinic Acetylcholine Receptors in Rat and Monkey Striatum (2012) · cites this paper as Grady et al., 2010
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“Indeed, a non-nicotine pharmaceutical currently FDA approved for the treatment of smoking cessation, varenicline, acts as a partial agonist at α6β2* nAChRs (Grady et al. 2010; Bordia et al. 2012).”
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Metadata
- 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)
- PMC
- PMC2849849
- 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
- green
- www.ncbi.nlm.nih.gov
- 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 › Public Health, Environmental and Occupational Health › 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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