Identification of an antagonist that selectively blocks the activity of prostamides (prostaglandin‐ethanolamides) in the feline iris

Identification of an antagonist that selectively blocks the activity of prostamides... Background and Purpose: The prostamides (prostaglandin‐ethanolamides) and prostaglandin (PG) glyceryl esters are biosynthesized by COX‐2 from the respective endocannabinoids anandamide and 2‐arachidonyl glycerol. Agonist studies suggest that their pharmacologies are unique and unrelated to prostanoid receptors. This concept was further investigated using antagonists. Experimental Approach: The isolated feline iris was used as a key preparation, where prostanoid FP receptors and prostamide activity co‐exist. Activity at human recombinant FP and other prostanoid receptors was determined using stable transfectants. Key Results: In the feline iris, AGN 204396 produced a rightward shift of the dose‐response curves for prostamide F2α and the prostamide F2α analog bimatoprost but did not block the effects of PGF2α and synthetic FP receptor agonists. Studies on human recombinant prostanoid receptors confirmed that AGN 204396 did not behave as a prostanoid FP receptor antagonist. AGN 204396 exhibited no antagonism at DP and EP1‐4, but was a highly effective TP receptor antagonist. Contrary to expectation, the FP receptor antagonist AL‐8810 efficaciously contracted the cat iris. AGN 204396 did not affect AL‐8810 induced contractions, demonstrating that AL‐8810 and AGN 204396 are pharmacologically distinct. Unlike AL‐8810, the ethylamide derivate of AL‐8810 was not an agonist. Al‐8810 did not block prostamide F2α activity. Finally, AGN 204396 did not block PGE2‐glyceryl ester activity. Conclusions and Implications: The ability of AGN 204396 to selectively block prostamide responses suggests the existence of prostamide sensitive receptors as entities distinct from receptors recognizing PGF2α and PGE2‐glyceryl ester. British Journal of Pharmacology (2007) 150, 342–352. doi:10.1038/sj.bjp.0706989 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png British Journal of Pharmacology Wiley

Identification of an antagonist that selectively blocks the activity of prostamides (prostaglandin‐ethanolamides) in the feline iris

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Publisher
Wiley
Copyright
2007 British Pharmacological Society
ISSN
0007-1188
eISSN
1476-5381
DOI
10.1038/sj.bjp.0706989
pmid
17179945
Publisher site
See Article on Publisher Site

Abstract

Background and Purpose: The prostamides (prostaglandin‐ethanolamides) and prostaglandin (PG) glyceryl esters are biosynthesized by COX‐2 from the respective endocannabinoids anandamide and 2‐arachidonyl glycerol. Agonist studies suggest that their pharmacologies are unique and unrelated to prostanoid receptors. This concept was further investigated using antagonists. Experimental Approach: The isolated feline iris was used as a key preparation, where prostanoid FP receptors and prostamide activity co‐exist. Activity at human recombinant FP and other prostanoid receptors was determined using stable transfectants. Key Results: In the feline iris, AGN 204396 produced a rightward shift of the dose‐response curves for prostamide F2α and the prostamide F2α analog bimatoprost but did not block the effects of PGF2α and synthetic FP receptor agonists. Studies on human recombinant prostanoid receptors confirmed that AGN 204396 did not behave as a prostanoid FP receptor antagonist. AGN 204396 exhibited no antagonism at DP and EP1‐4, but was a highly effective TP receptor antagonist. Contrary to expectation, the FP receptor antagonist AL‐8810 efficaciously contracted the cat iris. AGN 204396 did not affect AL‐8810 induced contractions, demonstrating that AL‐8810 and AGN 204396 are pharmacologically distinct. Unlike AL‐8810, the ethylamide derivate of AL‐8810 was not an agonist. Al‐8810 did not block prostamide F2α activity. Finally, AGN 204396 did not block PGE2‐glyceryl ester activity. Conclusions and Implications: The ability of AGN 204396 to selectively block prostamide responses suggests the existence of prostamide sensitive receptors as entities distinct from receptors recognizing PGF2α and PGE2‐glyceryl ester. British Journal of Pharmacology (2007) 150, 342–352. doi:10.1038/sj.bjp.0706989

Journal

British Journal of PharmacologyWiley

Published: Feb 1, 2007

References

  • Studies using isolated uterine and other preparations show bimatoprost and prostanoid FP agonists have different activity profiles
    Chen, Chen; Senior, Senior; Marshall, Marshall; Abbas, Abbas; Dinh, Dinh; Dinh, Dinh
  • Efficacy and safety of bimatoprost in patients with elevated intraocular pressure
    Dubiner, Dubiner; Cooke, Cooke; Dirks, Dirks; Stewart, Stewart; Vandenburgh, Vandenburgh; Felix, Felix
  • Bimatoprost and its free acid are prostaglandin FP receptor agonists
    Sharif, Sharif; Williams, Williams; Kelly, Kelly

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