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A. B. Kharlamb, S. N. Pettit, C. L. Cornell, J. L. Martos, H. G. Fliri, D. F. Woodward, J. W. Wang, L. A. Wheeler, M. E. Garst; Identification of Second Gneration Prostamide Antagonists ( AGN 211334-6). Invest. Ophthalmol. Vis. Sci. 2008;49(13):2611.
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The prostamides ( prostaglandin-ethanolamides ) and prostaglandin ( PG ) glyceryl esters are biosynthesized from the respective endocannabinoids anandamide and 2-arachidonyl glycerol via COX-2 . Early studies have suggested that the pharmacological profiles of prostamide Fα and PGE2 glyceryl ester are unique and unrelated to prostanoid receptors. This has recently been supported by the identificaiton of a selective prostamide antagonist AGN 204396. Here we report the activty of second generation prostamide antagonists AGN 211334,35,and 36.
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. Potent prostamide antagonists were designed by substituting the CH2 at position 3 with an oxygen.
The prostamide antagonists AGN 211334,35,36 did not block the prostanoid FP or other PG-sensitive receptors at concentrations up to 30µM. Similiary, in the cat iris, AGN 211334-6 did not block the effects of PGF2α. The effects of prostamide F2α in the cat iris were antagonized by AGN 211334,35, and 36 ; AGN 211334 being approximately 10 fold more potent than the protypical antagonist AGN 204396. I.C.50 values were AGN 211334=236nM, AGN 211335=356nM, AGN 211336=303nM, AGN 204396=2635nM
The identification of second generation prostamide antagonists provides further support for the prostamide receptor hypothesis. AGN 211334,35, and 36 and provided agents sufficiently potent for studies in living animals.
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