DT-0111: a novel drug-candidate for the treatment of COPD and chronic cough

Amir Pelleg, Fadi Xu, Jianguo Zhuang, Bradley J Undem, Geoffrey Burnstock

Research output: Contribution to journalArticle

Abstract

Background: Extracellular adenosine 5′-triphosphate (ATP) plays important mechanistic roles in pulmonary disorders in general and chronic obstructive pulmonary disease (COPD) and cough in particular. The effects of ATP in the lungs are mediated to a large extent by P2X2/3 receptors (P2X2/3R) localized on vagal sensory nerve terminals (both C and Aδ fibers). The activation of these receptors by ATP triggers a pulmonary-pulmonary central reflex, which results in bronchoconstriction and cough, and is also proinflammatory due to the release of neuropeptides from these nerve terminals via the axon reflex. These actions of ATP in the lungs constitute a strong rationale for the development of a new class of drugs targeting P2X2/3R. DT-0111 is a novel, small, water-soluble molecule that acts as an antagonist at P2X2/3R sites. Methods: Experiments using receptor-binding functional assays, rat nodose ganglionic cells, perfused innervated guinea pig lung preparation ex vivo, and anesthetized and conscious guinea pigs in vivo were performed. Results: DT-0111 acted as a selective and effective antagonist at P2X2/3R, that is, it did not activate or block P2YR; markedly inhibited the activation by ATP of nodose pulmonary vagal afferents in vitro; and, given as an aerosol, inhibited aerosolized ATP-induced bronchoconstriction and cough in vivo. Conclusions: These results indicate that DT-0111 is an attractive drug-candidate for the treatment of COPD and chronic cough, both of which still constitute major unmet clinical needs. The reviews of this paper are available via the supplementary material section.

Original languageEnglish (US)
JournalTherapeutic Advances in Respiratory Disease
Volume13
DOIs
StatePublished - Jan 1 2019

Fingerprint

Cough
Chronic Obstructive Pulmonary Disease
Purinergic P2X2 Receptors
Adenosine Triphosphate
Lung
Pharmaceutical Preparations
Bronchoconstriction
Therapeutics
Reflex
Guinea Pigs
Myelinated Nerve Fibers
Unmyelinated Nerve Fibers
Presynaptic Terminals
Drug Delivery Systems
Neuropeptides
Aerosols
Water

Keywords

  • asthma
  • ATP
  • bronchoconstriction
  • COPD
  • pulmonary inflammation
  • pulmonary-pulmonary reflex

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Pharmacology (medical)

Cite this

DT-0111 : a novel drug-candidate for the treatment of COPD and chronic cough. / Pelleg, Amir; Xu, Fadi; Zhuang, Jianguo; Undem, Bradley J; Burnstock, Geoffrey.

In: Therapeutic Advances in Respiratory Disease, Vol. 13, 01.01.2019.

Research output: Contribution to journalArticle

@article{37ef1826e40c4a06bbf6d6e5d4aa5497,
title = "DT-0111: a novel drug-candidate for the treatment of COPD and chronic cough",
abstract = "Background: Extracellular adenosine 5′-triphosphate (ATP) plays important mechanistic roles in pulmonary disorders in general and chronic obstructive pulmonary disease (COPD) and cough in particular. The effects of ATP in the lungs are mediated to a large extent by P2X2/3 receptors (P2X2/3R) localized on vagal sensory nerve terminals (both C and Aδ fibers). The activation of these receptors by ATP triggers a pulmonary-pulmonary central reflex, which results in bronchoconstriction and cough, and is also proinflammatory due to the release of neuropeptides from these nerve terminals via the axon reflex. These actions of ATP in the lungs constitute a strong rationale for the development of a new class of drugs targeting P2X2/3R. DT-0111 is a novel, small, water-soluble molecule that acts as an antagonist at P2X2/3R sites. Methods: Experiments using receptor-binding functional assays, rat nodose ganglionic cells, perfused innervated guinea pig lung preparation ex vivo, and anesthetized and conscious guinea pigs in vivo were performed. Results: DT-0111 acted as a selective and effective antagonist at P2X2/3R, that is, it did not activate or block P2YR; markedly inhibited the activation by ATP of nodose pulmonary vagal afferents in vitro; and, given as an aerosol, inhibited aerosolized ATP-induced bronchoconstriction and cough in vivo. Conclusions: These results indicate that DT-0111 is an attractive drug-candidate for the treatment of COPD and chronic cough, both of which still constitute major unmet clinical needs. The reviews of this paper are available via the supplementary material section.",
keywords = "asthma, ATP, bronchoconstriction, COPD, pulmonary inflammation, pulmonary-pulmonary reflex",
author = "Amir Pelleg and Fadi Xu and Jianguo Zhuang and Undem, {Bradley J} and Geoffrey Burnstock",
year = "2019",
month = "1",
day = "1",
doi = "10.1177/1753466619877960",
language = "English (US)",
volume = "13",
journal = "Therapeutic Advances in Respiratory Disease",
issn = "1753-4658",
publisher = "SAGE Publications Ltd",

}

TY - JOUR

T1 - DT-0111

T2 - a novel drug-candidate for the treatment of COPD and chronic cough

AU - Pelleg, Amir

AU - Xu, Fadi

AU - Zhuang, Jianguo

AU - Undem, Bradley J

AU - Burnstock, Geoffrey

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Background: Extracellular adenosine 5′-triphosphate (ATP) plays important mechanistic roles in pulmonary disorders in general and chronic obstructive pulmonary disease (COPD) and cough in particular. The effects of ATP in the lungs are mediated to a large extent by P2X2/3 receptors (P2X2/3R) localized on vagal sensory nerve terminals (both C and Aδ fibers). The activation of these receptors by ATP triggers a pulmonary-pulmonary central reflex, which results in bronchoconstriction and cough, and is also proinflammatory due to the release of neuropeptides from these nerve terminals via the axon reflex. These actions of ATP in the lungs constitute a strong rationale for the development of a new class of drugs targeting P2X2/3R. DT-0111 is a novel, small, water-soluble molecule that acts as an antagonist at P2X2/3R sites. Methods: Experiments using receptor-binding functional assays, rat nodose ganglionic cells, perfused innervated guinea pig lung preparation ex vivo, and anesthetized and conscious guinea pigs in vivo were performed. Results: DT-0111 acted as a selective and effective antagonist at P2X2/3R, that is, it did not activate or block P2YR; markedly inhibited the activation by ATP of nodose pulmonary vagal afferents in vitro; and, given as an aerosol, inhibited aerosolized ATP-induced bronchoconstriction and cough in vivo. Conclusions: These results indicate that DT-0111 is an attractive drug-candidate for the treatment of COPD and chronic cough, both of which still constitute major unmet clinical needs. The reviews of this paper are available via the supplementary material section.

AB - Background: Extracellular adenosine 5′-triphosphate (ATP) plays important mechanistic roles in pulmonary disorders in general and chronic obstructive pulmonary disease (COPD) and cough in particular. The effects of ATP in the lungs are mediated to a large extent by P2X2/3 receptors (P2X2/3R) localized on vagal sensory nerve terminals (both C and Aδ fibers). The activation of these receptors by ATP triggers a pulmonary-pulmonary central reflex, which results in bronchoconstriction and cough, and is also proinflammatory due to the release of neuropeptides from these nerve terminals via the axon reflex. These actions of ATP in the lungs constitute a strong rationale for the development of a new class of drugs targeting P2X2/3R. DT-0111 is a novel, small, water-soluble molecule that acts as an antagonist at P2X2/3R sites. Methods: Experiments using receptor-binding functional assays, rat nodose ganglionic cells, perfused innervated guinea pig lung preparation ex vivo, and anesthetized and conscious guinea pigs in vivo were performed. Results: DT-0111 acted as a selective and effective antagonist at P2X2/3R, that is, it did not activate or block P2YR; markedly inhibited the activation by ATP of nodose pulmonary vagal afferents in vitro; and, given as an aerosol, inhibited aerosolized ATP-induced bronchoconstriction and cough in vivo. Conclusions: These results indicate that DT-0111 is an attractive drug-candidate for the treatment of COPD and chronic cough, both of which still constitute major unmet clinical needs. The reviews of this paper are available via the supplementary material section.

KW - asthma

KW - ATP

KW - bronchoconstriction

KW - COPD

KW - pulmonary inflammation

KW - pulmonary-pulmonary reflex

UR - http://www.scopus.com/inward/record.url?scp=85072703998&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85072703998&partnerID=8YFLogxK

U2 - 10.1177/1753466619877960

DO - 10.1177/1753466619877960

M3 - Article

C2 - 31558105

AN - SCOPUS:85072703998

VL - 13

JO - Therapeutic Advances in Respiratory Disease

JF - Therapeutic Advances in Respiratory Disease

SN - 1753-4658

ER -