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.

Maresin 1 is a novel pro-resolving mediator derived from docosahexaenoic acid (DHA), with potent anti-inflammation effects against several animal models, including brain ischemia, sepsis, and lung fibrosis. However, its effect against motor neuron cell death is still not investigated. Therefore, we investigated the effects of maresin 1 on several stress-induced motor neuron cell death. Maresin 1 suppressed combinatorial stress which was evoked by superoxide dismutase 1 (SOD1) and serum-free, -induced motor neuron cells death in a concentration-dependent manner, and had a stronger neuroprotective effective than DHA. Maresin 1 also had neuroprotective effects against transactivation response DNA-binding protein (TDP)-43 and serum-free stress, HO, and tunicamycin-induced cell death. Maresin 1 reduced the reactive oxygen species (ROS) production caused by SOD1 or TDP-43. Moreover, maresin 1 suppressed the NF-κB activation induced by SOD1 and serum-free stress. These data indicate that maresin 1 has motor neuron protective effects against several stresses by reduction of ROS production or attenuation of the NF-κB activation. Maresin 1 also had neuroprotective effects against HO, and tunicamycin-induced cell death in a concentration-dependent manner. Finally, maresin 1 ameliorated the motor function deficits of spinal muscular atrophy model in which endoplasmic reticulum stress was upregulated. Thus, maresin 1 may be beneficial to protect against motor neuron diseases.

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

Exposure of rhodopsin to bright white light can induce photoreceptor cell damage and degeneration. However, a comprehensive understanding of the mechanisms underlying light-induced retinopathy remains elusive. In this study, we performed comparative transcriptome analysis of three rodent models of light-induced retinopathy, and we identified 37 genes that are dysregulated in all three models. Gene ontology analysis revealed that this gene set is significantly associated with a cytokine signaling axis composed of signal transducer and activator of transcription 1 and 3 (STAT1/3), interleukin 6 signal transducer (IL6ST), and oncostatin M receptor (OSMR). Furthermore, the analysis suggested that the histone acetyltransferase EP300 may be a key upstream regulator of the STAT1/3–IL6ST/OSMR axis. To examine the role of EP300 directly, we developed a larval zebrafish model of light-induced retinopathy. Using this model, we demonstrated that pharmacological inhibition of EP300 significantly increased retinal cell apoptosis, decreased photoreceptor cell outer segments, and increased proliferation of putative Müller cells upon exposure to intense light. These results suggest that EP300 may protect photoreceptor cells from light-induced damage and that activation of EP300 may be a novel therapeutic approach for the treatment of retinal degenerative diseases.