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OtherGastrointestinal, Hepatic, Pulmonary, and Renal

Evidence for alpha7 nicotinic receptor activation during the cough suppressing effects induced by nicotine and identification of ATA-101 as a potential novel therapy for the treatment of chronic cough

Brendan J. Canning, Qi Liu, Mayuko Tao, Robert DeVita, Michael Perelman, Douglas W Hay, Peter V Dicpinigaitis and Jing Liang
Journal of Pharmacology and Experimental Therapeutics November 15, 2021, JPET-AR-2021-000641; DOI: https://doi.org/10.1124/jpet.121.000641
Brendan J. Canning
1Medicine, Johns Hopkins Asthma and Allergy Center, United States
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  • For correspondence: bjc@jhmi.edu
Qi Liu
1Medicine, Johns Hopkins Asthma and Allergy Center, United States
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Mayuko Tao
2Tokyo Medical and Dental University, Japan
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Robert DeVita
3RJD Medicinal Chemistry Consulting LLC, United States
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Michael Perelman
4Michael Perelman Consulting, United States
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Douglas W Hay
5Hay Drug Discovery Consulting, United States
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Peter V Dicpinigaitis
6Albert Einstein College of Medicine, United States
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Jing Liang
7Apple Helix Bioventures, United States
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Abstract

Studies performed in healthy smokers have documented a diminished responsiveness to tussive challenges and several lines of experimental evidence implicate nicotine as an antitussive component in both cigarette smoke and the vapors generated by electronic cigarettes. We set out to identify the nicotinic receptor subtype involved in the antitussive actions of nicotine and to further evaluate the potential of nicotinic receptor-selective agonists as cough suppressing therapeutics. We confirmed an antitussive effect of nicotine in guinea pigs. We additionally observed that the α4β2-selective agonist Tc-6683 was without effect on evoked cough responses in guinea pigs, while the α7-selective agonist PHA 543613 dose-dependently inhibited evoked coughing. We subsequently describe the preclinical evidence in support of ATA-101, a potent and highly selective α7 selective nicotinic receptor agonist, as a potential candidate for antitussive therapy in humans. ATA-101, formerly known as Tc-5619, was orally bioavailable and moderately CNS penetrant and dose-dependently inhibited coughing in guinea pigs evoked by citric acid and bradykinin. Comparing the effects of airway targeted administration vs. systemic dosing and the effects of repeated dosing at various times prior to tussive challenge, our data suggest that the antitussive actions of ATA-101 require continued engagement of α7 nicotinic receptors, likely in the CNS. Collectively, the data provide the preclinical rationale for α7 nicotinic receptor engagement as a novel therapeutic strategy for cough suppression. The data also suggest that α7 nAChR activation by nicotine may be permissive to nicotine delivery in a way that may promote addiction.

Significance Statement This study documents the antitussive actions of nicotine and identifies the α7 nicotinic receptor subtype as the target for nicotine during cough suppression described in humans. We additionally present evidence suggesting that ATA-101 and other α7 nicotinic receptor selective agonists may be promising candidates for the treatment of chronic refractory cough.

  • addiction
  • cough
  • nicotine
  • nicotinic acetylcholine receptors
  • Copyright © 2020 American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 381 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 381, Issue 2
1 May 2022
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OtherGastrointestinal, Hepatic, Pulmonary, and Renal

Antitussive effects of alpha7 nicotinic receptor agonists

Brendan J. Canning, Qi Liu, Mayuko Tao, Robert DeVita, Michael Perelman, Douglas W Hay, Peter V Dicpinigaitis and Jing Liang
Journal of Pharmacology and Experimental Therapeutics November 15, 2021, JPET-AR-2021-000641; DOI: https://doi.org/10.1124/jpet.121.000641

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OtherGastrointestinal, Hepatic, Pulmonary, and Renal

Antitussive effects of alpha7 nicotinic receptor agonists

Brendan J. Canning, Qi Liu, Mayuko Tao, Robert DeVita, Michael Perelman, Douglas W Hay, Peter V Dicpinigaitis and Jing Liang
Journal of Pharmacology and Experimental Therapeutics November 15, 2021, JPET-AR-2021-000641; DOI: https://doi.org/10.1124/jpet.121.000641
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