Cited by 181Nicotinic Acetylcholine Receptors StudyRadiopharmaceutical Chemistry and ApplicationsNeuroscience and Neuropharmacology Research

5-Iodo-A-85380, an α4β2 Subtype-Selective Ligand for Nicotinic Acetylcholine Receptors

Mukhin, Alexey G., Gündisch, Daniela, Horti, Andrew G., Koren, Andrei O., Tamagnan, Gilles, Kimes, Alane S., Chambers, Joann, Vaupel, D. Bruce +4 more·2000·Molecular Pharmacology

Abstract

In an effort to develop selective radioligands for in vivo imaging of neuronal nicotinic acetylcholine receptors (nAChRs), we synthesized 5-iodo-3-(2(S)-azetidinylmethoxy)pyridine (5-iodo-A-85380) and labeled it with (125)I and (123)I. Here we present the results of experiments characterizing this radioiodinated ligand in vitro. The affinity of 5-[(125)I]iodo-A-85380 for alpha4beta2 nAChRs in rat and human brain is defined by K(d) values of 10 and 12 pM, respectively, similar to that of epibatidine (8 pM). In contrast to epibatidine, however, 5-iodo-A-85380 is more selective in binding to the alpha4beta2 subtype than to other nAChR subtypes. In rat adrenal glands, 5-iodo-A-85380 binds to nAChRs containing alpha3 and beta4 subunits with 1/1000th the affinity of epibatidine, and exhibits 1/60th and 1/190th the affinity of epibatidine at alpha7 and muscle-type nAChRs, respectively. Moreover, unlike epibatidine and cytisine, 5-[(125)I]iodo-A-85380 shows no binding in any brain regions in mice homozygous for a mutation in the beta2 subunit of nAChRs. Binding of 5-[(125)I]iodo-A-85380 in rat brain is reversible, and is characterized by high specificity and a slow rate of dissociation of the receptor-ligand complex (t(1/2) for dissociation approximately 2 h). These properties, along with other features observed previously in in vivo experiments (low toxicity, rapid penetration of the blood-brain barrier, and a high ratio of specific to nonspecific binding), suggest that this compound, labeled with (125)I or (123)I, is superior to other radioligands available for in vitro and in vivo studies of alpha4beta2 nAChRs, respectively.

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Crossref · 10.1124/mol.57.3.642

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  • [123I]5-IA is a nicotinic agonist that binds with high affinity to the nicotine binding site on nAChRs that contain the β2-subunit.

    “[123I]5-IA is a nicotinic agonist that binds with high affinity to the nicotine binding site on nAChR that contain the β2-subunit39.”

    From β2-Nicotinic Acetylcholine Receptor Availability During Acute and Prolonged Abstinence From Tobacco Smoking (2009) · cites this paper as [39]

    The available indexed passages are BindingDB ligand listings (no section or page given), not passages describing the paper’s receptor-binding or functional findings. Searches for 5-iodo-A-85380 agonism, β2-containing receptors, and the nicotine binding site found no passage that establishes the claim. (LLM, conf=0.72)

    Experimental — accuracy not yet measured
  • Nicotine competes with [123I]5-IA binding for binding to nAChRs.

    “Because nicotine competes with [ 123 I]5-IA binding for binding to nAChRs (Mukhin et al., 2000)”

    From Human Tobacco Smokers in Early Abstinence Have Higher Levels of β<sub>2</sub>* Nicotinic Acetylcholine Receptors than Nonsmokers (2006) · cites this paper as Mukhin et al., 2000

    The available indexed passages (no section or page labels) list nicotine and 5-iodo-A-85380 as receptor ligands, but do not describe nicotine competing with [123I]5-IA for binding. Searches for nicotine displacement, inhibition, and competitive binding returned no passage addressing that relationship. (LLM, conf=0.70)

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Authors
Mukhin, A. G., Gündisch, D., Horti, A. G., Koren, A. O., Tamagnan, G., Kimes, A. S., Chambers, J., Vaupel, D. B., King, S. L., Picciotto, M. R., Innis, R. B., & London, E. D.
Affiliations
National Institute on Drug Abuse (US)
Venue
Molecular Pharmacology
Publisher
Elsevier BV
Published
2000-03-01
Volume
57
Issue
3
Pages
642-649
ISSN
  • 0026-895X (ISSN-L)
  • 1521-0111
OpenAlex
W2158847001
Cited by
173
References
47
Citations by year
2026: 2 · 2025: 1 · 2024: 1 · 2023: 2 · 2022: 1 · 2020: 1 · 2018: 5 · 2016: 2 · 2015: 7 · 2014: 4 · 2013: 10 · 2012: 8
FWCI
3.50
Type
journal article
Language
en
Open access
closed
Locations
  • Molecular Pharmacology (publishedVersion)
  • PubMed (publishedVersion)
Funders
Eunice Kennedy Shriver National Institute of Child Health and Human Development (N01 HD 13138)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
  • Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Radiopharmaceutical Chemistry and Applications
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
nicotinic acetylcholine receptors, radioligands, iodine-125 labeling, epibatidine, receptor binding affinity, receptor dissociation kinetics
MeSH terms
Animals, Azetidines, Binding, Competitive, Brain, Humans, Iodine Radioisotopes, Male, Rats, Inbred F344, Receptors, Nicotinic, Tissue Distribution, Rats, Sprague-Dawley, Mice, Rats, In Vitro Techniques

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