Identification of the primary products of cyclo-oxygenase (COX)/prostaglandin synthase(s), which occurred between 1958 and 1976, was followed by a classification system for prostanoid receptors (DP, EP1, EP2 . . .) based mainly on the pharmacological actions of natural and synthetic agonists and a few antagonists. The design of potent selective antagonists was rapid for certain prostanoid receptors (EP1, TP), slow for others (FP, IP) and has yet to be achieved in certain cases (EP2). While some antagonists are structurally related to the natural agonist, most recent compounds are 'non-prostanoid' (often acyl-sulphonamides) and have emerged from high-throughput screening of compound libraries, made possible by the development of (functional) assays involving single recombinant prostanoid receptors. Selective antagonists have been crucial to defining the roles of PGD2 (acting on DP1 and DP2 receptors) and PGE2 (on EP1 and EP4 receptors) in various inflammatory conditions; there are clear opportunities for therapeutic intervention. The vast endeavour on TP (thromboxane) antagonists is considered in relation to their limited pharmaceutical success in the cardiovascular area. Correspondingly, the clinical utility of IP (prostacyclin) antagonists is assessed in relation to the cloud hanging over the long-term safety of selective COX-2 inhibitors. Aspirin apart, COX inhibitors broadly suppress all prostanoid pathways, while high selectivity has been a major goal in receptor antagonist development; more targeted therapy may require an intermediate position with defined antagonist selectivity profiles. This review is intended to provide overviews of each antagonist class (including prostamide antagonists), covering major development strategies and current and potential clinical usage.

We investigated whether prostaglandin ethanolamides (prostamides) E 2 , F 2␣ , and D 2 exert some of their effects by 1) activating prostanoid receptors either per se or after conversion into the corresponding prostaglandins; 2) interacting with proteins for the inactivation of the endocannabinoid N-arachidonoylethanolamide (AEA), for example fatty acid amide hydrolase (FAAH), thereby enhancing AEA endogenous levels; or 3) activating the vanilloid receptor type-1 (TRPV1). Prostamides potently stimulated cat iris contraction with potency approaching that of the corresponding prostaglandins. However, prostamides D 2 , E 2 , and F 2␣ exhibited no meaningful interaction with the cat recombinant FP receptor, nor with human recombinant DP, EP 1-4 , FP, IP, and TP prostanoid receptors. Prostamide F 2␣ was also very weak or inactive in a panel of bioassays specific for the various prostanoid receptors. None of the prostamides inhibited AEA enzymatic hydrolysis by FAAH in cell homogenates, or AEA cellular uptake in intact cells. Furthermore, less than 3% of the compounds were hydrolyzed to the corresponding prostaglandins when incubated for 4 h with homogenates of rat brain, lung, or liver, and cat iris or ciliary body. Very little temperature-dependent uptake of prostamides was observed after incubation with rat brain synaptosomes or RBL-2H3 cells. We suggest that prostamides' most prominent pharmacological actions are not due to transformation into prostaglandins, activation of prostanoid receptors, enhancement of AEA levels, or gating of TRPV1 receptors, but possibly to interaction with novel receptors that seem to be functional in the cat iris.

1 The aim of this study was to establish the role of nitric oxide (NO) and cyclic GMP in chemotaxis and superoxide anion generation (SAG) by human neutrophils, by use of selective inhibitors of NO and cyclic GMP pathways. In addition, inhibition of neutrophil chemotaxis by NO releasing compounds and increases in neutrophil nitrate/nitrite and cyclic GMP levels were examined. The ultimate aim of this work was to resolve the paradox that NO both activates and inhibits human neutrophils. 2 A role for NO as a mediator of N-formyl-methionyl-leucyl-phenylalanine (fMLP)-induced chemotaxis was supported by the ®nding that the NO synthase (NOS) inhibitor L-NMMA (500 mM) inhibited chemotaxis; EC 50 for fMLP 28.76+5.62 and 41.13+4.77 pmol/10 6 cells with and without L-NMMA, respectively. Similarly the NO scavenger carboxy-PTIO (100 mM) inhibited chemotaxis; EC 50 for fMLP 19.71+4.23 and 31.68+8.50 pmol/10 6 cells with and without carboxy-PTIO, respectively. 3 A role for cyclic GMP as a mediator of chemotaxis was supported by the ®nding that the guanylyl cyclase inhibitor LY 83583 (100 mM) completely inhibited chemotaxis and suppressed the maximal response; EC 50 for fMLP 32.53+11.18 and 85.21+15.14 pmol/10 6 cells with and without LY 83583, respectively. The same pattern of inhibition was observed with the G-kinase inhibitor KT 5823 (10 mM); EC 50 for fMLP 32.16+11.35 and 4135 pmol/10 6 cells with and without KT 5823, respectively. 4 The phosphatase inhibitor, 2,3-diphosphoglyceric acid (DPG) (100 mM) which inhibits phospholipase D, attenuated fMLP-induced chemotaxis; EC 50 for fMLP 19.15+4.36 and 61.52+16.2 pmol/10 6 cells with and without DPG, respectively. 5 Although the NOS inhibitors L-NMMA and L-canavanine (500 mM) failed to inhibit fMLP-induced SAG, carboxy-PTIO caused signi®cant inhibition (EC 50 for fMLP 36.15+7.43 and 86.31+14.06 nM and reduced the maximal response from 22.14+1.5 to 9.8+1.6 nmol O 2 7 /10 6 cells/10 min with and without carboxy-PTIO, respectively). This suggests NO is a mediator of fMLP-induced SAG. 6 A role for cyclic GMP as a mediator of SAG was supported by the e ects of G-kinase inhibitors KT 5823 (10 mM) and Rp-8-pCPT-cGMPS (100 mM) which inhibited SAG giving EC 50 for fMLP of 36.26+8.77 and 200.01+43.26 nM with and without KT 5823, and 28.35+10.8 and 49.25+16.79 nM with and without Rp-8-pCTP-cGMPS. 7 The phosphatase inhibitor DPG (500 mM) inhibited SAG; EC 50 for fMLP 33.93+4.23 and 61.12+14.43 nM with and without DPG, respectively. 8 The NO releasing compounds inhibited fMLP-induced chemotaxis with a rank order of potency of GEA 3162 (IC 50 =14.72+1.6 mM)4GEA 5024 (IC 50 =18.44+0.43 mM)4SIN-1 (IC 50 41000 mM). This order of potency correlated with their ability to increase cyclic GMP levels rather than the release of NO, where SIN-1 was most e ective (SIN-1 (EC 50 =37.62+0.9 mM)4GEA 3162 (EC 50 =39.7+0.53 mM)4 GEA 5024 (EC 50 =89.86+1.62 mM)). 9 In conclusion, chemotaxis and SAG induced by fMLP can be attenuated by inhibitors of phospholipase D, NO and cyclic GMP, suggesting a role for the...

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