Molecular Pharmacology, Vol 13, 38-43, Copyright © 1977 by the American Society for Pharmacology and Experimental Therapeutics

Effects of Antiallergic Agents, Compound 48/80, and Some Reference Inhibitors on the Activity of Partially Purified Human Lung Tissue Adenosine Cyclic 3',5'-Monophosphate and Guanosine Cyclic 3',5'-Monophosphate Phosphodiesterases

¹ Research and Development Laboratories, AB Draco, Fack, S-221 01 Lund, Sweden

Various compounds, some of which influence immediate allergic reactions in different ways, were examined for inhibitory effects on partially purified human lung tissue cyclic nucleotide phosphodiesterases. Some of the compounds reported to possess antiallergic properties were found to be more potent as inhibitors of a low-K_m, cyclic 3',5'-GMP-specific phosphodiesterase than of a corresponding low-K_m, cyclic 3',5'-AMP-specific enzyme. For 2-o-propoxyphenyl-8-azapurin-6-one (M & B 22,948), 6-n-butyl-2,8-dicarboxy-4,10-dioxo-1,4,7,10-tetrahydro-1,7-phenanthroline (ICI 74,917), and disodium cromoglycate this selectivity was remarkable; to produce 50% inhibition of enzyme activity, a 10-100-fold lower concentration of these agents was required with the former enzyme than with the latter. Compound 48/80, on the other hand, showed high selectivity as an inhibitor of the cyclic AMP-specific, low-K_m phosphodiesterase. Among the reference phosphodiesterase inhibitors examined, theophylline, 3-isobutyl-1-methylxanthine, and papaverine inhibited both low-K_m enzymes to a comparable degree, whereas 4-(3-butoxy-4-methoxybenzyl)-2-imidazolidinone (Ro 20-1724) was pronouncedly more active toward the cyclic AMP-specific enzyme. Most compounds examined also inhibited the activity of a high-K_m phosphodiesterase which hydrolyzes cyclic AMP and cyclic GMP at comparable rates. Pronounced inhibitory potency was recorded for Dicumarol, doxantrazole, compound 48/80, and papaverine, whereas M & B 22,948 was only slightly effective with this enzyme.

Note:
ACKNOWLEDGMENTS We thank our colleagues at Draco for valuable discussions, and Drs. H. Schüller and H. Henriksson, who kindly provided human lung tissue specimens.

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