Prostaglandin E2-Glyceryl Ester: In Vivo Evidence for a Distinct Pharmacological Identity from Intraocular Pressure Studies

Abstract

Prostaglandin E 2 (PGE 2 )-2-glyceryl ester is a cyclo-oxygenase 2 product of the endocannabinoid 2-arachidonyl glycerol. It is claimed as pharmacologically novel, but this is complicated by rapid and irreversible isomerization to the 1(3) ester. For ocular studies, enzymatic hydrolysis of the ester moiety creates an additional complication. PG-glyceryl esters were stabilized to isomerization and hydrolysis by replacing the noncarbonyl O with NH, to form the serinolamide and propanediolamide as stable analogs of PG-2-glyceryl and PG-2-1(3) glyceryl esters, respectively. Intraocular pressure was measured in conscious dogs and conscious laser-induced ocular hypertensive monkeys. Pharmacological studies involved stable transfectants for each of the human recombinant prostanoid receptors and the isolated feline iris for prostamide activity. PGE 2 -serinolamide and PGE 2 -propanediolamide were essentially inactive at all receptors except the EP 3 receptor (EC 50 , ∼500 nM). This obliged elucidation of EP 3 receptor involvement in the intraocular pressure response to these PGE 2 -glycyerl ester analogs. Since the EP 3 receptor agonists sulprostone and GR 63799 did not lower monkey intraocular pressure, a role for EP 3 receptors in mediating the effects of PGE 2 -serinolamide and PGE 2 -propanediolamide is not indicated. PGE 2 -glyceryl ester (0.01% and 0.1%) substantially lowered intraocular pressure in monkeys. PGE 2 -propanediolamide was more efficacious than PGE 2 -serinolamide in lowering intraocular pressure in monkey eyes, but both appeared equieffective in dog eyes. PGE 2 -serinolamide dose-dependently (0.01-0.1%) lowered intraocular pressure in both species, but PGF 2a -serinolamide was inactive. In conclusion, stable PGE 2 -glyceryl ester analogs lowered intraocular pressure. These findings are consistent with the presence of a PGE 2 -glyceryl ester-specific recognition site in the eye.

Mapping the Binding Sites of UDP and Prostaglandin E2 Glyceryl Ester in the Nucleotide Receptor P2Y6

“… [2b] UDP has been shown to lower intraocular pressure via activation of P2Y 6 expressed in the ciliary body making the receptor a promising target for glaucoma treatment. [14] Interestingly, PGE 2 ‐G also reduces intraocular pressure in dogs and monkeys, [15] and one can speculate that this effect is mediated via P2Y 6 .…”