Prostanoid receptor EP2 as a therapeutic target

Abstract

Cycoloxygenase-2 (COX-2) induction is prevalent in a variety of (brain and peripheral) injury models where COX-2 levels correlate with disease progression. Thus, COX-2 has been widely explored for anti-inflammatory therapy with COX-2 inhibitors, which proved to be effective in reducing the pain and inflammation in patients with arthritis and menstrual cramps, but they have not provided any benefit to patients with chronic inflammatory neurodegenerative disease. Recently, two COX-2 drugs, rofecoxib and valdecoxib, were withdrawn from the United States market due to cardiovascular side effects. Thus, future anti-inflammatory therapy could be targeted through a specific prostanoid receptor downstream of COX-2. The PGE2 receptor EP2 is emerging as a pro-inflammatory target in a variety of CNS and peripheral diseases. Here we highlight the latest developments on the role of EP2 in diseases, mechanism of activation, and small molecule discovery targeted either to enhance or to block the function of this receptor.

Figure 1

COX/prostaglandin signaling cascade. Arachidonic acid is converted to PGG₂ and then to PGH₂ by both COX-1 and COX-2 enzymes. Cell specific synthases convert the intermediate PGH₂ into prostaglandin ligands, which activate one or more G coupled-prostanoid receptors. There are four receptors DP1, EP2, EP4 and IP which promote cAMP production. cAMP then activates PKA-, and Epac-signaling. COX-2 inhibitor (red) would block every prostanoid receptor type, but an EP2 antagonist (blue) could block only one out of eleven prostanoid receptors and may avoid COX-2 inhibition mediated side-effects.

Figure 2

PGE₂ via EP2-receptor stimulates the differentiation of Th0 to Th17, which exacerbates the disease progression and severity in peripheral diseases such as arthritis and IBD. Additional EP2 signaling is shown in Figure 5

Figure 3

EP2 receptors are involved in a variety of CNS and peripheral diseases. EP2 receptors shown to play a protective role in models of stroke, bone-fracture and glaucoma. But, mouse models of cancer, endometriosis, AD, PD, ALS, arthritis and IBD suggest EP2 promotes inflammatory cascade or exacerbates disease pathology. Thus EP2 may be targeted for discovery of therapeutics for these diseases.

Figure 4

Structures of EP2 agonists, EP2 allosteric potentiator and EP2 antagonists

Figure 5

EP2 mediates both beneficial and deleterious effects by G protein-coupled and G protein-independent downstream mechanisms. Upon PGE₂ binding, EP2 activates and dissociates Gαs protein. Then Gαs regulates activities of various effectors. Abbreviations used; PKA = protein kinase A, CREB = cAMP responsive binding element protein, PI3K = phosphatidylinositol-3-kinase, ERK = extracellular signal regulated kinase, JNK = c-Jun N-terminal kinase, EGFR = epidermal growth factor receptor.

Figure 6

General structural scaffolds of EP2 antagonists reported in the patent literature. EP2 inhibition activity range from nanomolar to micromolar among the members in each class, is shown here for comparison purposes.

Figure 7

Two potential therapeutic strategies that may be useful for EP2 receptor mediated effects in the brain for neuroprotection and for blocking the neurodegeneration