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D.F. Woodward; First Report on a Prostamide Antagonist (AGN 204396): Evidence for Prostamide and Prostaglandin FP Receptors as Discrete Entities in the Feline Iris . Invest. Ophthalmol. Vis. Sci. 2005;46(13):2416.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: The prostamides (prostaglandin – ethanolamides) and prostaglandin (PG) glyceryl esters are biosynthesized from the respective endocannabinoids anandamide and 2 – arachidonyl glycerol. Early studies have suggested that the pharmacological profiles of prostamide F2α and PGE2 glyceryl ester are unique and unrelated to prostanoid receptors. These previous studies relied on comparisons of agonist activity. The aim of the present studies was to further investigate the prostamide receptor concept by evaluating receptor antagonists. Methods: Effects on human recombinant PG receptors were studied using a FLIPR instrument: stable co–transfection of cDNAs encoding the receptors and a chimeric G protein allowed functional activity to be assessed as a Ca2+ signal for all receptors. The isolated feline iris was used as a key preparation where prostanoid FP receptor and prostamide activity co–exist. Results: The prostamide antagonist AGN 204396 did not block the prostanoid FP or other PG–sensitive receptors at concentrations up to 30µM. Similarly, in the cat iris, AGN 204396 did not block the effects of PGF2α, 17–phenyl PGF2α and other selective FP receptor agonists. The effects of prostamide F2a and its analog bimatoprost in the cat iris were antagonized by AGN204396, indicating that AGN 204396 is a selective prostamide receptor antagonist. The FP receptor antagonist AL–8810 was also evaluated in an attempt to selectively block FP receptors in the feline iris but it efficaciously contracted the tissue and was, therefore, unsuitable for antagonist studies. AGN 204396 did not affect AL–8810 induced contraction. Finally, AGN 204396 did not block the effects of PGE2–glyceryl ester. Conclusions: The identification of a prostamide antagonist provides further support for the prostamide receptor hypothesis. Further evidence that prostamide receptors are distinct from prostanoid receptors was provided by AGN 204396 which selectively blocked the effects of prostamide F2α and bimatoprost in the cat iris, but had no effect on responses to PGF2α and its analogs. Prostamide receptors also appear distinct from the proposed PGE2– glyceryl ester receptors.
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