We performed this study to determine if curcumin affects pro-inflammatory responses to activation of proteinase-activated receptor-2 (PAR2) in human pulmonary adenocarcinoma A549 cells. Curcumin completely inhibited the PAR2-triggered prostaglandin E(2) (PGE(2)) production, but notably not interleukin-8 release. Cyclooxygenase-2 (COX-2) upregulation, but not its upstream activation of mitogen-activated protein kinases, caused by PAR2 stimulation was partially inhibited by curcumin. Curcumin inhibited the PAR2-triggered phosphorylation of I-κB, an indicator for nuclear factor-κB (NF-κB) activation, and also its upstream signal Akt, which is known to contribute to PAR2-triggered PGE(2) formation, but not COX-2 upregulation. Collectively, curcumin inhibits the PAR2-triggered PGE(2) production by suppressing COX-2 upregulation and Akt/NF-κB signals in A549 cells.

A more profound and longer-lasting reduction in IOP in normotensive monkeys can be observed with ONO-9054, which simultaneously stimulates both EP3 and FP receptors, compared with prostaglandin analogs.

We investigated possible involvement of three isozymes of prostaglandin E synthase (PGES), microsomal PGES-1 (mPGES-1), mPGES-2 and cytosolic PGES (cPGES) in COX-2-dependent prostaglandin E(2) (PGE(2)) formation following proteinase-activated receptor-2 (PAR2) stimulation in human lung epithelial cells. PAR2 stimulation up-regulated mPGES-1 as well as COX-2, but not mPGES-2 or cPGES, leading to PGE(2) formation. The PAR2-triggered up-regulation of mPGES-1 was suppressed by inhibitors of COX-1, cytosolic phospholipase A(2) (cPLA(2)) and MEK, but not COX-2. Finally, a selective inhibitor of mPGES-1 strongly suppressed the PAR2-evoked PGE(2) formation. PAR2 thus appears to trigger specific up-regulation of mPGES-1 that is dependent on prostanoids formed via the MEK/ERK/cPLA(2)/COX-1 pathway, being critical for PGE(2) formation.

To identify G protein-biased and highly subtype-selective EP2 receptor agonists, a series of bicyclic prostaglandin analogues were designed and synthesized. Structural hybridization of EP2/4 dual agonist 5 and prostacyclin analogue 6, followed by simplification of the ω chain enabled us to discover novel EP2 agonists with a unique prostacyclin-like scaffold. Further optimization of the ω chain was performed to improve EP2 agonist activity and subtype selectivity. Phenoxy derivative 18a showed potent agonist activity and excellent subtype selectivity. Furthermore, a series of compounds were identified as G protein-biased EP2 receptor agonists. These are the first examples of biased ligands of prostanoid receptors. KEYWORDS: Prostaglandin, EP2, agonist, biased ligand, structure−functional selectivity relationship P rostaglandin E 2 (PGE 2 ) is an oxidative metabolite of arachidonic acid that exerts a wide variety of biological actions through four receptor subtypes, EP1−EP4, in various tissues. The EP2 receptor has been characterized by relaxation of blood vessels.1 Furthermore, EP2 receptor plays important roles in cytokine production and bone metabolism.2,3 It has also been reported that activation of EP2 receptor led to neuroprotective effects in ischemic stroke models.4−8 EP2 receptor receives a lot of attention as a therapeutic target for various diseases.A number of EP2 agonists have previously been reported.9−15 The PGE 2 analogue, butaprost (1), is wellknown as a selective EP2 agonist and is widely used as a chemical tool compound in many studies on pharmacological activities mediated by EP2 receptor (Figure 1). In previous studies, we developed the highly selective and chemically stable EP2 agonist, 2, 10 which is a good tool compound for EP2 receptor. A number of nonprostanoid scaffolds of EP2 agonists have also been reported to show potent EP2 agonist activity (for example, PF-4217329 3 13 and 4 15 ). In recent studies by Pfizer, PF-4217329 3, an isopropyl ester, showed remarkable intraocular pressure lowering effects in primary open-angle glaucoma and ocular hypertension. 16 To date, however, there is no EP2 agonist that is approved for clinical use. Although the true reasons for the suspension of clinical trials of EP2 agonists are not clear, we assume that a variety of biological actions induced by EP2 agonists caused crucial side effects for clinical use.Recently, biased ligands have received a fair amount of attention in drug discovery