AH6809, a prostaglandin DP-receptor blocking drug on human platelets.
1. The effect of AH6809 (6-isopropoxy-9-oxoxanthene-2-carboxylic acid) has been studied upon the anti-aggregatory and aggregatory actions of various agents on human platelets in whole blood. 2. Prostaglandin D2 (PGD2), BW245C, 9 alpha, 11 beta-PGF2, PGI2 and 5'-N-ethylcarboxamide adenosine (NECA) all inhibited ADP-induced platelet aggregation in whole blood. The anti-aggregatory activity of PGD2, BW245C and 9 alpha, 11 beta-PGF2 but not PGI2 or NECA was antagonized by AH6809. NECA was antagonized by AH6809. 3. The antagonism of the anti-aggregatory activity of PGD2 by AH6809 was concentration-related and could be overcome by increasing the concentration of PGD2. Analysis of the data yielded an apparent pA2 for AH6809 of 5.35. 4. At approximately 10 fold higher concentrations than those required to antagonize the action of PGD2, AH6809 also antagonized the aggregatory effect of U-46619 in whole blood (pA2 = 4.45). However, concentrations of AH6809 up to 300 microM were without effect upon either ADP- or platelet activating factor (Paf)-induced aggregation (pA2 less than 3.5). 5. The potency of AH6809 against PGD2 and U-46619 was increased in a resuspended platelet preparation suggesting that the drug is extensively bound to plasma proteins. However, in resuspended platelets the specificity of AH6809 relative to that seen in whole blood was reduced since aggregation by ADP and Paf was also slightly antagonized. 6. In conclusion, AH6809 appears to be a weak but specific DP-receptor blocking drug on human platelets and should prove to be a useful drug tool for defining the involvement of endogenous PGD2 in platelet aggregation and classifying the mode of action of anti-aggregatory prostanoids.
Keery
R J
RJ
Department of Cardiovascular Pharmacology, Glaxo Group Research Ltd, Ware, Herts.
Lumley
P
P
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D000244:Adenosine Diphosphate / Q000494:pharmacology; D019830:Adenosine-5'-(N-ethylcarboxamide); D015237:Dinoprost / Q000037:antagonists & inhibitors; D011464:Epoprostenol / Q000494:pharmacology; D006801:Humans; D006827:Hydantoins / Q000037:antagonists & inhibitors; D066298:In Vitro Techniques; D008297:Male; D010972:Platelet Activating Factor / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects*; D015230:Prostaglandin D2 / Q000037:antagonists & inhibitors; D011450:Prostaglandin Endoperoxides, Synthetic / Q000037:antagonists & inhibitors; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin / Q000187:drug effects*; D014966:Xanthenes / Q000494:pharmacology*; D044004:Xanthones
D006827:Hydantoins; D010972:Platelet Activating Factor; D011450:Prostaglandin Endoperoxides, Synthetic; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; D014966:Xanthenes; D044004:Xanthones; C053876:6-isopropoxy-9-oxoxanthene-2-carboxylic acid; D019830:Adenosine-5'-(N-ethylcarboxamide); D000244:Adenosine Diphosphate; C030669:BW 245C; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D015237:Dinoprost; D011464:Epoprostenol; D000241:Adenosine; D015230:Prostaglandin D2; D015056:1-Methyl-3-isobutylxanthine; C036293:prostaglandin D2 receptor