TY - JOUR
T1 - 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
AU - Canning, Brendan J.
AU - Liu, Qi
AU - Tao, Mayuko
AU - DeVita, Robert
AU - Perelman, Michael
AU - Hay, Douglas W.
AU - Dicpinigaitis, Peter V.
AU - Liang, Jing
N1 - Publisher Copyright:
© 2022 by The American Society for Pharmacology and Experimental Therapeutics.
PY - 2022/2/1
Y1 - 2022/2/1
N2 - 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 (eCigs). 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 alpha-4 beta-2 (a4b2)-selective agonist Tc-6683 was without effect on evoked cough responses in guinea pigs, while the a7-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 (a7) 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 central nervous system (CNS) penetrant and dose-dependently inhibited coughing in guinea pigs evoked by citric acid and bradykinin. Comparing the effects of airway targeted administration versus 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 a7 nicotinic receptors, likely in the CNS. Collectively, the data provide the preclinical rationale for a7 nicotinic receptor engagement as a novel therapeutic strategy for cough suppression. The data also suggest that a7 nicotinic acetylcholine receptor (nAChR) activation by nicotine may be permissive to nicotine delivery in a way that may promote addiction.
AB - 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 (eCigs). 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 alpha-4 beta-2 (a4b2)-selective agonist Tc-6683 was without effect on evoked cough responses in guinea pigs, while the a7-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 (a7) 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 central nervous system (CNS) penetrant and dose-dependently inhibited coughing in guinea pigs evoked by citric acid and bradykinin. Comparing the effects of airway targeted administration versus 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 a7 nicotinic receptors, likely in the CNS. Collectively, the data provide the preclinical rationale for a7 nicotinic receptor engagement as a novel therapeutic strategy for cough suppression. The data also suggest that a7 nicotinic acetylcholine receptor (nAChR) activation by nicotine may be permissive to nicotine delivery in a way that may promote addiction.
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U2 - 10.1124/jpet.121.000641
DO - 10.1124/jpet.121.000641
M3 - Article
C2 - 34782407
AN - SCOPUS:85123812605
SN - 0022-3565
VL - 380
SP - 94
EP - 103
JO - Journal of Pharmacology and Experimental Therapeutics
JF - Journal of Pharmacology and Experimental Therapeutics
IS - 2
ER -