Abstract

Prostaglandin D₂ (PGD₂) is a mast cell-derived mediator that seems to play a role in asthma and allergic diseases. It is the only primary prostanoid to activate human eosinophils, which it accomplishes through the DP₂receptor/chemoattractant receptor-homologous molecule expressed on T helper cell type 2 (Th2) cells (CRTH2). In addition, PGD₂has both pro- and anti-inflammatory effects via the adenylyl cyclase-coupled DP₁ receptor. To attempt to identify potent and selective DP₂ receptor agonists we compared the abilities of a series of PGD₂ analogs to activate eosinophils via the DP₂ receptor with their abilities to stimulate adenylyl cyclase in platelets via the DP₁receptor. All of the PGD₂ analogs tested stimulated CD11b expression and actin polymerization with a rank order of potency of 15R-methyl-PGD₂ > PGD₂ > 17-phenyl-18,19,20-trinor-PGD₂ > 15S-methyl-PGD₂ ≈ 16,16-dimethyl-PGD₂ > 11-keto-fluprostenol. Surprisingly, 15R-methyl-PGD₂, which has the unnatural R -configuration at carbon 15, was about 5 times more potent than PGD₂ and about 75 times more potent than 15S-methyl-PGD₂. 15R-methyl-PGD₂(EC₅₀ value of 1.7 nM) was also much more potent as an eosinophil chemoattractant than PGD₂(EC₅₀ value of 10 nM) and 15S-methyl-PGD₂(EC₅₀ value of 128 nM). Cross-desensitization experiments indicated that 15R-methyl-PGD₂ acts through the DP₂ receptor. None of the PGD₂ analogs tested elevated platelet cAMP by more than 20% of the maximal level in response to PGD₂. However, in contrast to eosinophils, the most active was 15S-methyl-PGD₂. In conclusion, 15R-methyl-PGD₂ is the most potent known DP₂ receptor agonist, and because of its selectivity and resistance to metabolism, should be a useful tool in probing the physiological role of this receptor in inflammatory diseases.