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

Bergstrand, H.; Kristoffersson, J.; Lundquist, B.; Schurmann, A.

Molecular Pharmacology 13(1): 38-43


ISSN/ISBN: 0026-895X
PMID: 189182
Accession: 068523407

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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 more potent as inhibitors of a low-Km, cyclic 3',5'-GMP-specific phosphodiesterase than of a corresponding low-Km, cyclic 3',5'-AMP-specific enzyme. For 2-o-propoxyphenyl-8-azapurin-6-one (M and 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 to 100-fold lower concentration of these agents was required with the former enzyme than with the latter. Compound 48/80 showed high selectivity as an inhibitor of the cAMP-specific, low-Km, phosphodiesterase. Among the reference phosphodiesterase inhibitors examined, theophylline, 3-isobutyl-1-methylxanthine and papaverine inhibited both low-Km enzymes to a comparable degree, whereas 4-(3-butoxy-4-methoxybenzyl)-2-imidazolidinone (Ro 20-1724) was pronouncedly more active toward the cAMP-specific enzyme. Most compounds examined also inhibited the activity of a high-Km phosphodiesterase which hydrolyzes cAMP and cGMP at comparable rates. Pronounced inhibitory potency was recorded for Dicumarol, doxantrazole, compound 48/80 and papaverine, whereas M and B 22,948 was only slightly effective with this enzyme.