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 F2alpha and the prostamide F2alpha analog bimatoprost but did not block the effects of PGF2alpha 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 F2alpha 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 PGF2alpha and PGE2-glyceryl ester.
Subject(s)
Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Dinoprost/analogs & derivatives , Dinoprostone/analogs & derivatives , Dinoprostone/pharmacology , Iris/drug effects , Oxazoles/pharmacology , Animals , Cats , Dinoprost/pharmacology , Dinoprost/physiology , Dinoprostone/physiology , Dose-Response Relationship, Drug , In Vitro Techniques , Receptors, Prostaglandin/drug effects , Recombinant ProteinsABSTRACT
An equilibrating diastereomer mixture of the tertiary phosphines 5 and 6 (2.5:1 equilibrium ratio) undergoes crystallization-induced asymmetric transformation upon slow evaporation of solvent from refluxing heptane to give a 20:1 ratio in favor of the more stable crystalline isomer 5. The process can also be carried out at room temperature by using iodine to catalyze the interconversion of 5 and 6 via a pentavalent intermediate 8. However, this variation is more sensitive to the purity of the starting phosphine. Crystalline 5 can be converted to the stable borane complex 3, and reductive cleavage of the fluorenyl group using lithium naphthalenide affords the corresponding lithio derivative 10. Alkylation with iodomethane or benzyl bromide affords 13 or 17, respectively, with retention of phosphorus configuration.
