title: Discovery of a potent and long-acting bronchorelaxing capsazepinoid, RESPIR 4-95.
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 TRPV1 antagonism and independent of current bronchodilator drug mechanisms.
  
  
  METHODS
  In vitro preparations of human small airways, 0.5-1.5mm in diameter and responding with reproducible contractions to leukotriene D4 (LTD4) for 12h, were used.
  
  
  RESULTS
  RESPIR 4-95 reversibly prevented LTD4-induced contractions as well as relaxed the established tonic contraction by LTD4. 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 LTD4-, histamine-, prostaglandin D2 (PGD2)-, 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.
  
  
  CONCLUSIONS
  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.
authors: Respiratorius AB, Magistratsvägen 10, 226 43 Lund, Sweden.
authors: Staffan
authors: S
authors: Skogvall
authors: María F
authors: MF
authors: Dalence-Guzmán
authors: Magnus
authors: M
authors: Berglund
authors: Katrin
authors: K
authors: Svensson
authors: Admira
authors: A
authors: Mesic
authors: Per
authors: P
authors: Jönsson
authors: Carl G A
authors: CG
authors: Persson
authors: Olov
authors: O
authors: Sterner
mesh_terms: D058666:Adrenergic beta-2 Receptor Agonists; D001993:Bronchodilator Agents / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002211:Capsaicin / Q000031:analogs & derivatives / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D066298:In Vitro Techniques; D017998:Leukotriene D4 / Q000494:pharmacology; D008168:Lung / Q000187:drug effects* / Q000502:physiology; D009119:Muscle Contraction / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects* / Q000502:physiology; D044005:Tetrahydroisoquinolines / Q000494:pharmacology*
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; D001993:Bronchodilator Agents; D002121:Calcium Channel Blockers; C528448:RESPIR 4-95; D044005:Tetrahydroisoquinolines; C014843:1,2,3,4-tetrahydroisoquinoline; D017998:Leukotriene D4; C071423:capsazepine; D002211:Capsaicin