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

Skogvall, Staffan; Dalence, Maria LU ; Berglund, Magnus LU ; Svensson, Katrin; Mesic, Admira; Jönsson, Per LU ; Persson, Carl G.A. and Sterner, Olov LU (2008) In Pulmonary Pharmacology & Therapeutics 21(1). p.125-133
Abstract
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... (More)
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. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Bronchorelaxant, COPD, Human small airways, Asthma, Capsazepinoids, RESPIR 4-95
in
Pulmonary Pharmacology & Therapeutics
volume
21
issue
1
pages
125 - 133
publisher
Elsevier
external identifiers
  • pmid:17374498
  • wos:000262943300019
  • scopus:38049024386
ISSN
1522-9629
DOI
10.1016/j.pupt.2007.01.004
language
English
LU publication?
yes
id
1e04d733-0529-4176-901b-221eae9432ca (old id 1138802)
date added to LUP
2008-04-29 09:54:32
date last changed
2017-01-01 05:26:37
@article{1e04d733-0529-4176-901b-221eae9432ca,
  abstract     = {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.},
  author       = {Skogvall, Staffan and Dalence, Maria and Berglund, Magnus and Svensson, Katrin and Mesic, Admira and Jönsson, Per and Persson, Carl G.A. and Sterner, Olov},
  issn         = {1522-9629},
  keyword      = {Bronchorelaxant,COPD,Human small airways,Asthma,Capsazepinoids,RESPIR 4-95},
  language     = {eng},
  number       = {1},
  pages        = {125--133},
  publisher    = {Elsevier},
  series       = {Pulmonary Pharmacology & Therapeutics},
  title        = {Discovery of a potent and long-acting bronchorelaxing capsazepinoid, RESPIR 4-95},
  url          = {http://dx.doi.org/10.1016/j.pupt.2007.01.004},
  volume       = {21},
  year         = {2008},
}