Prostaglandin E2 (PGE2)-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. PGE2-serinolamide and PGE2- propanediolamide were essentially inactive at all receptors except the EP3 receptor (EC50, ∼500 nM). This obliged elucidation of EP3 receptor involvement in the intraocular pressure response to these PGE2-glycyerl ester analogs. Since the EP3 receptor agonists sulprostone and GR 63799 did not lower monkey intraocular pressure, a role for EP3 receptors in mediating the effects of PGE2-serinolamide and PGE2-propanediolamide is not indicated. PGE2-glyceryl ester (0.01% and 0.1%) substantially lowered intraocular pressure in monkeys. PGE2-propanediolamide was more efficacious than PGE2-serinolamide in lowering intraocular pressure in monkey eyes, but both appeared equieffective in dog eyes. PGE2-serinolamide dose-dependently (0.01- 0.1%) lowered intraocular pressure in both species, but PGF2 α-serinolamide was inactive. In conclusion, stable PGE2-glyceryl ester analogs lowered intraocular pressure. These findings are consistent with the presence of a PGE2-glyceryl ester-specific recognition site in the eye.

2010-08-01·American Journal of Physiology-Cell Physiology3区 · 生物学

PGE₂ promotes Ca²⁺-mediated epithelial barrier disruption through EP₁ and EP₄ receptors in Caco-2 cell monolayers

3区 · 生物学

Article

作者: Ferrer, Ruth ; Rodríguez-Lagunas, M. José ; Moreno, Juan José ; Martín-Venegas, Raquel

We recently demonstrated that PGE2 induces the disruption of the intestinal epithelial barrier function. In the present study, our objectives were to study the role of PGE2 receptors (EP1–EP4) and the signaling pathways involved in this event. Paracellular permeability (PP) was assessed in differentiated Caco-2 cell cultures from d-mannitol fluxes and transepithelial electrical resistance (TER) in the presence of different PGE2 receptor agonists (carbacyclin, sulprostone, butaprost, ONO-AE1-259, ONO-AE-248, GR63799, and ONO-AE1-329) and antagonists (ONO-8711, SC-19220, AH-6809, ONO-AE3-240, ONO-AE3-208, and AH-23848). The results indicate that EP1 and EP4 but not EP2 and EP3 might be involved in PP regulation. These effects were mediated through PLC-inositol trisphosphate (IP3)-Ca2+ and cAMP-PKA signaling pathways, respectively. We also observed an increase in intracellular Ca2+ concentration ([Ca2+]i) strengthened by cAMP formation indicating a cross talk interaction of these two pathways. Moreover, the participation of a conventional PKC isoform was shown. The results also indicate that the increase in PP may be correlated with the redistribution of occludin, zona occludens 1 (ZO-1), and the perijunctional actin ring together with an increase in myosin light chain kinase activity. Although the disruption of epithelial barrier function observed in inflammatory bowel disease (IBD) patients has been traditionally attributed to cytokines, the present study focused on the role of PGE2 in PP regulation, as mucosal levels of this eicosanoid are also increased in these inflammatory processes.

2010-02-18·Journal of Pharmacy and Pharmacology3区 · 医学

Pharmacological characterization and identification of EP3 prostanoid receptor binding sites in hamster uterus homogenates

3区 · 医学

Article

作者: Xu, S X ; Sharif, N A

AbstractThe pharmacological properties of [3H]-prostaglandin E2 ([3H]-PGE2) binding to washed homogenates of hamster uterus were determined. Scatchard analysis of competition data yielded dissociation constants (Kds) of 30.9 + 5.6 nm (n = 3) and apparent receptor density (Bmax) of 25.25 + 1.89 pmol g−1 wet weight tissue (74 + 8% specific binding). Competition studies yielded the following affinity parameters (Ki) for various prostanoids: GR63799X = 13 + 4 nm; PGE2 = 17 + 3 nm; sulprostone = 64 + 5 nm; enprostil = 67 + 3 nm; misoprostol = 124 + 15 nm; cloprostenol = 187 + 33 nm; carba-prostacyclin = 260 + 167 nm; iloprost = 555 + 162 nm; PGF2α = 767 + 73 nm; PGD2 > 3560 nm; fluprostenol = 11790 + 2776 nm; RS93520 = 21 558 + 14228 nm. These data closely matched the pharmacological profile of previously described EP3 receptors such as in bovine corpus luteum (BCLM) and the cloned mammalian EP3 receptors. The high correlation between the current hamster uterus pharmacology data vs the EP3 receptor binding in BCLM (r = 0.94; P < 0.0001), vs cloned human EP3 receptor (r = 0.94, P < 0.0001), vs the cloned mouse EP3 receptor binding (r = 0.78; P < 0.002), vs cloned rat EP3 receptor (r = 0.9, P < 0.0004), and vs EP3 receptor-mediated functional responses (r = 0.72, P < 0.02) substantiated the conclusion that the hamster uterus contains EP3 receptor binding sites.

100 项与 GR-63799 相关的药物交易

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