Identification of 19 (R)-OH prostaglandin E2 as a selective prostanoid EP2-receptor agonist.
The physiological significance of the formation of large quantities of 19(R)-hydroxy prostaglandin E's (19-OH PGE) from PGE1 and PGE2 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 PGE2, which may indiscriminately stimulate a variety of prostanoid receptor subtypes, 19(R)-OH PGE2 exhibited selectivity for the EP2-receptor subtype. In EP1 (guinea pig ileum contraction), EP2 (cat trachea relaxation), and EP3 (chick ileum contraction) preparations where PGE2 is equipotent, 19(R)-OH PGE2 exhibited greater potency in the EP2-receptor population. Moreover, unlike PGE2, 19(R)-OH PGE2 did not stimulate an FP-receptor preparation (cat iris). 19(R)-OH PGE2 was devoid of activity at thromboxane A2-(TP), prostaglandin D2-(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 PGE1 had an entirely converse profile of activity. As a myotropic agent in the guinea pig and chick ileal preparations, 19(R)-OH PGE1 was approximately 1.5 orders of magnitude more potent than 19(R)-OH PGE2 but it appeared devoid of EP2-receptor stimulant properties. 19(R)-OH PGF2 alpha possessed very little biological activity in a diverse variety of isolated tissue preparations, indicating that 19-hydroxylation represents a highly efficient inactivation step for PGF2 alpha. The implications of the formation of receptor selective PGE derivatives in human seminal fluid for human reproductive physiology remains to be established.
Woodward
D F
DF
Department of Biological Sciences, Allergan Pharmaceuticals, Irvine, California 92713-9534.
Protzman
C E
CE
Krauss
A H
AH
Williams
L S
LS
D000244:Adenosine Diphosphate / Q000494:pharmacology; D000818:Animals; D002415:Cats; D002645:Chickens; D015232:Dinoprostone / Q000031:analogs & derivatives* / Q000494:pharmacology; D006168:Guinea Pigs; D006801:Humans; D007082:Ileum / Q000187:drug effects / Q000502:physiology; D009119:Muscle Contraction / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects; D018078:Receptors, Prostaglandin E / Q000187:drug effects / Q000502:physiology*; D014132:Trachea / Q000187:drug effects / Q000502:physiology
D018078:Receptors, Prostaglandin E; C048823:19-hydroxyprostaglandin E2; D000244:Adenosine Diphosphate; D015232:Dinoprostone