Prostaglandin E Receptor 4 Antagonist in Cancer Immunotherapy: Mechanisms of Action.

A highly expressed prostaglandin E (PGE) in tumor tissues suppresses antitumor immunity in the tumor microenvironment (TME) and causes tumor immune evasion leading to disease progression. In animal studies, selective inhibition of the prostaglandin E receptor 4 (EP4), one of four PGE receptors, suppresses tumor growth, restoring the tumor immune response toward an antitumorigenic condition. This review summarizes PGE/EP4 signal inhibition in relation to the cancer-immunity cycle (C-IC), which describes fundamental tumor-immune interactions in cancer immunotherapy.

Pharmacology of grapiprant, a novel EP4 antagonist: receptor binding, efficacy in a rodent postoperative pain model, and a dose estimation for controlling pain in dogs.

Grapiprant is an analgesic and anti-inflammatory drug in the piprant class that was approved in March 2016 by FDA's Center for Veterinary Medicine for the control of pain and inflammation associated with osteoarthritis (OA) in dogs. Grapiprant functions as a selective antagonist of the EP4 receptor, one of the four prostaglandin E (PGE ) receptor subtypes. The EP4 receptor mediates PGE -elicited nociception, and grapiprant has been shown to decrease pain in several rat inflammatory pain models.

Adenosine kinase inhibitors. 6. Synthesis, water solubility, and antinociceptive activity of 5-phenyl-7-(5-deoxy-beta-D-ribofuranosyl)pyrrolo[2,3-d]pyrimidines substituted at C4 with glycinamides and related compounds.

4-(Phenylamino)-5-phenyl-7-(5-deoxy-beta-D-ribofuranosyl)pyrrolo[2,3-d]pyrimidine 1 and related compounds known as "diaryltubercidin" analogues are potent inhibitors of adenosine kinase (AK) and are orally active in animal models of pain such as the rat formalin paw model (GP3269 ED50= 6.4 mg/kg). However, the utility of this compound class is limited by poor water solubility that can be attributed to the high energy of crystallization caused by stacking of the parallel C4 and C5 aryl rings in the solid state (compound 1 and GP3269 each with pH 7.

Histological study of granulated metrial gland (GMG) cells in beige (DA-bg/bg) rats.

To clarify the roles of granulated metrial gland (GMG) cells for successful pregnancy in rats, GMG cells in beige rats (genotype: DA-bg/bg), whose NK cells show lysosomal dysfunction because of abnormalities in cytoplasmic granules, were examined in mid- and late-pregnancy by light and electron microscopies. The GMG cells of beige rats were significantly less in number than those of the two controls (genotypes: DA-bg/+ and DA-+/+) in mid- and late-pregnancy, and this accompanied a low reproductive performance in the beige rats. The size of intracellular granules in the GMG cells of the beige rats was larger than for the two controls on each corresponding day of pregnancy.

Adenosine kinase inhibitors. 5. Synthesis, enzyme inhibition, and analgesic activity of diaryl-erythro-furanosyltubercidin analogues.

Adenosine is an endogenous neuromodulator that when produced in the central and the peripheral nervous systems has anticonvulsant, anti-inflammatory, and analgesic properties. However, efforts to use adenosine receptor agonists are plagued by dose-limiting cardiovascular side effects. As an alternative, we explored the use of adenosine kinase inhibitors (AKIs) as potential antiseizure agents and demonstrated an adenosine receptor mediated therapeutic effect in the absence of overt cardiovascular side effects.