title: Anti-tussive and bronchodilator mechanisms of action for the enaminone E121.
abstract: OBJECTIVE
  In this study, we investigated whether the enaminone, E121, has anti-tussive effects in a guinea pig model of cough, and if so, whether this effect is mediated via a central or peripheral site of action. We also assessed whether E121 has bronchodilator effects and the molecular mechanisms underlying any anti-tussive and/or bronchodilator effects.
  
  
  METHODS
  Whole body plethysmography was used to assess both cough and airway obstruction. A stereotaxic apparatus was used to administer drugs intracerebroventricularly (i.c.v.). Effects of E121 were examined in vitro on contractile effects in guinea pig bronchioles.
  
  
  RESULTS
  Pre-treatment of animals with E121 resulted in a significant inhibition in the citric acid-induced cough and airway obstruction compared to vehicle-pretreated animals. The K(ATP) antagonist, glibenclamide, significantly inhibited the anti-tussive and bronchoprotective effects of E121. Also, intra-tracheal administration of E121 resulted in a significant inhibition of both the citric acid-induced cough response and airway obstruction compared to vehicle-pretreated animals. By contrast, i.c.v. administration had no effect. Finally, E121 significantly inhibited carbachol-induced airway smooth muscle contractions, an effect that was reduced by both glibenclamide and propranolol. Interestingly, E121 enhanced histamine-induced cAMP release in human eosinophils although it did not directly elevate cAMP levels.
  
  
  CONCLUSIONS
  The enaminone, E121, has anti-tussive and bronchodilatory effects and is topically, but not centrally, active. The anti-tussive mechanism of action of E121 seems to be K(ATP) channel dependent, whereas its bronchodilatory effects appear to be mediated via activation of both K(ATP) channels and β(2) receptors. Therefore, E121 may potentially represent a novel therapy for cough, particularly cough associated with airway obstruction.
authors.affiliation: Department of Applied Therapeutics, Faculty of Pharmacy, Kuwait University, Kuwait. ahmed.elhashim@hsc.edu.kw
authors.forename: Ahmed Z
authors.initials: AZ
authors.lastname: El-Hashim
authors.forename: Ivan O
authors.initials: IO
authors.lastname: Edafiogho
authors.forename: Sahar M
authors.initials: SM
authors.lastname: Jaffal
authors.forename: Mariam H
authors.initials: MH
authors.lastname: Yousif
authors.forename: Charles I
authors.initials: CI
authors.lastname: Ezeamuzie
authors.forename: Samuel B
authors.initials: SB
authors.lastname: Kombian
mesh_terms: D000280:Administration, Inhalation; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000402:Airway Obstruction / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D000814:Aniline Compounds / Q000009:adverse effects / Q000494:pharmacology*; D000818:Animals; D000996:Antitussive Agents / Q000009:adverse effects / Q000494:pharmacology*; D001993:Bronchodilator Agents / Q000009:adverse effects / Q000494:pharmacology*; D019343:Citric Acid / Q000009:adverse effects; D003371:Cough / Q000139:chemically induced / Q000188:drug therapy*; D000242:Cyclic AMP / Q000032:analysis; D003509:Cyclohexanecarboxylic Acids / Q000009:adverse effects / Q000494:pharmacology*; D004195:Disease Models, Animal; D004804:Eosinophils / Q000187:drug effects; D005260:Female; D005905:Glyburide / Q000494:pharmacology*; D006168:Guinea Pigs; D057967:Infusions, Intraventricular; D054086:KATP Channels / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008297:Male; D010991:Plethysmography; D011433:Propranolol / Q000494:pharmacology; D011897:Random Allocation
chemical_list: D000319:Adrenergic beta-Antagonists; D000814:Aniline Compounds; D000996:Antitussive Agents; D001993:Bronchodilator Agents; D003509:Cyclohexanecarboxylic Acids; C483746:E 121 compound; D054086:KATP Channels; D019343:Citric Acid; D011433:Propranolol; D000242:Cyclic AMP; D005905:Glyburide