Antiallergic activity profiles in vitro of RHC 3164 and related compounds. I. A lack of correlation between inhibition of cyclic nucleotide phosphodiesterases and antigen-induced release of histamine from rat mast cells.
A series of 26 compounds belonging to the chemical class of (1,2,4)triazolo(4,3-a)-quinoxaline-1,4-diones have been investigated for their antiallergic activities in 3 in vitro models of anaphylaxis. Effects of these and other known antiallergic agents on cyclic nucleotide phosphodiesterases (cNUC-PDE) from purified rat mast cells have also been investigated. 18 compounds were potent (I50 less than or equal to 45 microM) inhibitors of antigen-induced release of histamine (AIR) from rat mast cells (RMC), 3 compounds inhibited anti-IgE-induced release of histamine from human basophils (I50 less than or equal to 25 microM) and none of the compounds significantly affected AIR from guinea pig lung slices. 13 of the compounds were more potent than theophylline as inhibitors of cyclic AMP-PDE and/or cyclic GMP-PDE from RMC. Parallel concentration-response curves for the inhibition of cyclic AMP-PDE and cyclic GMP-PDE indicated that these compounds probably interact with enzyme in the same manner. Paired regression analysis of the I50 values for inhibition of AIR and cNUC-PDE from RMC by these compounds revealed no statistically significant correlation between the inhibition of AIR and inhibition of cyclic AMP-PDE or cyclic GMP-PDE. We conclude: (1) some of these compounds are potent inhibitors of immunologic release of histamine from RMC with an in vitro activity profile similar to that of DSCG, and (2) inhibition of cyclic AMP or cyclic GMP hydrolysis by cNUD-PDE by these compounds, DSCG, and 6 known antiallergic agents is not the biochemical mechanism by which they inhibit AIR from RMC.
D015087:2',3'-Cyclic-Nucleotide Phosphodiesterases / Q000037:antagonists & inhibitors*; D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors; D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000502:physiology; D000941:Antigens / Q000276:immunology; D001491:Basophils / Q000276:immunology; D004205:Cromolyn Sodium / Q000494:pharmacology; D003864:Depression, Chemical; D006168:Guinea Pigs; D006634:Histamine H1 Antagonists / Q000494:pharmacology*; D006636:Histamine Release / Q000187:drug effects*; D006801:Humans; D006967:Hypersensitivity / Q000188:drug therapy*; D007073:Immunoglobulin E / Q000276:immunology / Q000502:physiology; D007700:Kinetics; D008168:Lung / Q000276:immunology; D008297:Male; D008407:Mast Cells / Q000276:immunology; D010047:Ovalbumin / Q000276:immunology; D010726:Phosphodiesterase Inhibitors; D010727:Phosphoric Diester Hydrolases; D051381:Rats; D011919:Rats, Inbred Strains; D014230:Triazoles / Q000494:pharmacology*
D000888:Antibodies, Anti-Idiotypic; D000941:Antigens; D006634:Histamine H1 Antagonists; D010726:Phosphodiesterase Inhibitors; D014230:Triazoles; C026408:anti-IgE antibodies; D007073:Immunoglobulin E; C040270:7-chloro-5-propyl-1,2,4-triazolo(4,3-a)quinoxaline-1,4(2H,5H)-dione; D010047:Ovalbumin; D015087:2',3'-Cyclic-Nucleotide Phosphodiesterases; D010727:Phosphoric Diester Hydrolases; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D004205:Cromolyn Sodium