Discovery of a potent and long-acting bronchorelaxing capsazepinoid, RESPIR 4-95.
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.
Skogvall
Staffan
S
Respiratorius AB, Magistratsvägen 10, 226 43 Lund, Sweden.
Dalence-Guzmán
María F
MF
Berglund
Magnus
M
Svensson
Katrin
K
Mesic
Admira
A
Jönsson
Per
P
Persson
Carl G A
CG
Sterner
Olov
O
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*
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