RHC 2963 (7-methyl-pyrido (3',2':4,5)-thieno (3,2-d)-1,2,3
triazine-4(3H)-one and 20 related compounds have been investigated for their
antiallergic activities in 3 in vitro models of
anaphylaxis and for their effects on
cyclic nucleotide phosphodiesterases (cNUC-PDE) from purified rat mast cells (RMC). Nine compounds were potent (I50 less than or equal to 80 microM) inhibitors of
antigen-induced release of
histamine (AIR) from RMC, 2 compounds inhibited
anti-IgE-induced release of
histamine from human basophils (I50 less than or equal to 60 microM) and one compound inhibited AIR from guinea pig lung slices (I50 = 55 microM).
RHC 2963 was 18 times more potent than
disodium cromoglycate (DSCG) as inhibitor of AIR from RMC and had an activity profile identical to that of DSCG in the following respects: loss of inhibitory activity with increasing preincubation time, tachyphylactic properties and inability to inhibit non-immunologic release of
histamine induced by
compound 48/80. Neither
RHC 2963 nor DSCG had any effect on
anti-IgE-induced release of
histamine from human basophils or
IgG1-mediated release of
histamine from guinea pig lung. Twelve of the compounds in this chemical series were more potent than
theophylline as inhibitors of
cyclic AMP and/or
cyclic GMP phosphodiesterase (PDE) from RMC. Paired regression analysis of the I50 values for inhibition of AIR and cNUC-PDE from RMC revealed no statistically significant correlation between the inhibition of AIR and inhibition of cAMP- or cGMP-PDE. We conclude: (1)
RHC 2963 and some of the related compounds are potent inhibitors of immunologic release of
histamine from RMC with a mechanism of action similar to that of DSCG, and (2) inhibition of cAMP- or cGMP-PDE by these compounds is not the biochemical mechanism by which they inhibit AIR from RMC.