Identification of 19 (R)-OH prostaglandin E 2 as a selective prostanoid EP 2-receptor agonist

Abstract

The physiological significance of the formation of large quantities of 19(R)-hydroxy prostaglandin E's (19-OH PGE) from PGE 1 and PGE 2 in human seminal plasma is intriguing. The concept that prostaglandins exert their biological effects by interacting with specific receptors, according to the current working classification for prostanoid receptors, was employed as a conceptual framework to re-examine the activity of 19(R)-OH PG's. In contrast to PGE 2, which may indiscriminately stimulate a variety of prostanoid receptor subtypes, 19(R)-OH PGE 2 exhibited selectivity for the EP 2-receptor subtype. In EP 1 (guinea pig ileum contraction), EP 2 (cat trachea relaxation), and EP 3 (chick ileum contraction) preparations where PGE 2 is equipotent, 19(R)-OH PGE 2 exhibited greater potency in the EP 2- receptor population. Moreover, unlike PGE 2, 19(R)-OH PGE 2 did not stimulate an FP-receptor preparation (cat iris). 19(R)-OH PGE 2 was devoid of activity at thromboxane A 2-(TP), prostaglandin D 2-(DP) and prostacyclin-(IP) sensitive receptors as indicated by its inability to cause human platelet aggregation or inhibit ADP-induced platelet aggregation. 19(R)-OH PGE 1 had an entirely converse profile of activity. As a myotropic agent in the guinea pig and chick ileal preparations, 19(R)-OH PGE 1 was approximately 1.5 orders of magnitude more potent than 19(R)-OH PGE 2 but it appeared devoid of EP 2-receptor stimulant properties. 19(R)-OH PGF 2α possessed very little biological activity in a diverse variety of isolated tissue preparations, indicating that 19-hydroxylation represents a highly efficient inactivation step for PGF 2α. The implications of the formation of receptor selective PGE derivatives in human seminal fluid for human reproductive physiology remains to be established.