Agonist and Antagonist Effects of 15R-Prostaglandin (PG) D₂and 11-Methylene-PGD₂on Human Eosinophils and Basophils

Abstract

Prostaglandin (PG) D 2 acts through both the DP 1 receptor, which is coupled to adenylyl cyclase, and the DP 2 receptor (chemoattractant receptor-homologous molecule expressed on Th2 cells), which is present on eosinophils, basophils, and Th2 cells and results in cell activation and migration. The most potent prostanoid DP 2 agonist so far reported is 15R-methyl-PGD 2 , in which the hydroxyl group has the unnatural R configuration. In contrast, the corresponding analog possessing the natural 15S configuration is ϳ75 times less potent. This raised the question of whether the isoprostane 15R-PGD 2 might have potent DP 2 receptor-mediated biological activity. We therefore chemically synthesized 15R-PGD 2 and investigated its biological activity. This compound elicited DP 2 receptor-mediated CD11b expression in human basophils and eosinophils and induced actin polymerization and migration in eosinophils with a potency about the same as that of PGD 2 . In contrast, it had only a weak effect on DP 1 receptor-mediated adenylyl cyclase activity in human platelets. We also investigated the effects of modification of the 9-hydroxyl and 11-oxo groups of PGD 2 . Both PGK 2 , in which the 9-hydroxyl group is replaced by an oxo group, and 11-deoxy-11-methylene PGD 2 , in which the 11-oxo group is replaced by a CH 2 group, have little or no DP 1 or DP 2 agonist activity. However, the 11-methylene analog is a DP 2 antagonist (IC 50 , ϳ2 M). We conclude that 15R-PGD 2 , which may be generated by oxidative stress, is a potent and selective DP 2 agonist and that modification of the 11-oxo group of PGD 2 can result in DP 2 antagonist activity.

Prostaglandin D 2 Inhibits Hair Growth and Is Elevated in Bald Scalp of Men with Androgenetic Alopecia

“…S3). For example, the weak agonist 11-deoxy-11-methylene PGD 2 (28) had the lowest activity (hair growth inhibition) of the compounds tested. Note that GPR44 has nanomolar affinities for ligands, but as is typical for this type of experiment, higher concentrations were required to overcome tissue penetration and compound lysis.…”

International Union of Basic and Clinical Pharmacology. LXXXIII: Classification of Prostanoid Receptors, Updating 15 Years of Progress

“…An important role for DP 2 receptors in chronic cutaneous inflammation was revealed in DP 2 -deficient mice (Satoh et al, 2006). Prostaglandin D 2 also activates basophils via DP 2 receptors (Hirai et al, 2001;Cossette et al, 2007). A final comment on the roles of DP 1 and DP 2 in regulating allergy/inflammation Pettipher, 2008): the employment of a DP 2 antagonist may switch PGD 2 from a pro-to an antiinflammatory mediator in many instances.…”

“…The 15S stereochemistry is atypically not crucial to DP 2 agonism, with 15R-and 15R-15-methyl PGD 2 showing high DP 2 /DP 1 selectivity (Jones, 1976(Jones, ,a,b, 1978Monneret et al, 2001Monneret et al, , 2003Kim et al, 2005;Cossette et al, 2007). Moreover, 15-oxo structures (usually considered to be bioinactive products of 15-hydroxy PG dehydrogenase) retain high DP 2 agonism.…”

“…The variance allowed at C15 is not unlimited, however; 15S-15-methyl PGD 2 shows only weak DP 2 agonism (Monneret et al, 2003). Finally, replacement of the 11-oxo group in PGD 2 by methylene essentially abolishes DP 1 agonism and results in weak DP 2 antagonism (Cossette et al, 2007). DP 2 antagonists have been a major focus for drug discovery in recent years.…”

Application of lipid peroxidation products as biomarkers for flutamide-induced oxidative stress in vitro

“…Especially isomers from the F-ring (dihydroxypentan) class have been investigated extensively. However, recent studies also showed that isomers from the Dand E-ring group (hydroxypentanon) can serve as biomarkers and bioactive substances (Cossette et al, 2007;Brose et al, 2011).…”