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Discovery of a potent and long-acting bronchorelaxing capsazepinoid, RESPIR 4-95

Author:
  • Staffan Skogvall
  • Maria Dalence
  • Magnus Berglund
  • Katrin Svensson
  • Admira Mesic
  • Per Jönsson
  • Carl G.A. Persson
  • Olov Sterner
Publishing year: 2008
Language: English
Pages: 125-133
Publication/Series: Pulmonary Pharmacology & Therapeutics
Volume: 21
Issue: 1
Document type: Journal article
Publisher: Elsevier

Abstract english

BACKGROUND: Current drugs including beta-agonists have limited smooth muscle relaxant effects on human small airways. Yet this is a major site of obstruction in asthma and chronic obstructive pulmonary disease (COPD). OBJECTIVE: This study explores human small airway relaxant effects of RESPIR 4-95, a novel chemical analogue (capsazepinoid) to capsazepine. Capsazepine was recently shown to relax small airways in a way which was independent of its TRPV(1) antagonism and independent of current bronchodilator drug mechanisms. METHOD: In vitro preparations of human small airways, 0.5-1.5mm in diameter and responding with reproducible contractions to leukotriene D(4) (LTD(4)) for 12h, were used. RESULTS: RESPIR 4-95 reversibly prevented LTD(4)-induced contractions as well as relaxed the established tonic contraction by LTD(4). RESPIR 4-95 exhibited marked improvements over the reference capsazepinoid, capsazepine, by being 10 times more potent, exhibiting twice as long duration of action after wash-out (9h), and inhibiting equally well LTD(4)-, histamine-, prostaglandin D(2) (PGD(2))-, and acetylcholine (ACh)-induced contractions. RESPIR 4-95 was distinguished from l-type calcium channel antagonist nifedipine by its greater efficacy and potency and by exhibiting increased relaxant effect by repeated exposures. Furthermore, RESPIR 4-95 was more efficacious and longer acting than the long-acting beta-agonist formoterol. CONCLUSION: Efficacy, potency, duration of action, and inexhaustibility of its relaxation of human small airways make RESPIR 4-95 an interesting lead compound for further developments aiming at drug treatment of small airway obstruction in asthma and COPD. Further work is warranted to unveil the molecular biology behind its relaxant actions.

Keywords

  • Surgery
  • Medicinal Chemistry
  • Cardiac and Cardiovascular Systems
  • Pharmacology and Toxicology
  • Bronchorelaxant
  • COPD
  • Human small airways
  • Asthma
  • Capsazepinoids
  • RESPIR 4-95

Other

Published
  • ISSN: 1522-9629
Olov Sterner
E-mail: olov.sterner [at] science.lu.se

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