Inhibition of separated forms of cyclic nucleotide phosphodiesterase from pig coronary arteries by 1,3-disubstituted and 1,3,8-trisubstituted xanthines

Abstract

A series of xanthines with varied substituents in the 1, 3 and 8 positions were prepared to understand the structure-activity relationship for alkylxanthines (theophylline, caffeine and 1-methyl-3-isobutylxanthine) as inhibitors of 2 different forms of cyclic nucleotide phosphodiesterase. Polar substituents on the 1 or 3 position of the xanthine reduced the potency of the xanthines to inhibit both the calmodulin-sensitive and the cAMP specific forms of phosphodiesterase. Polar substituents on the 8 position of the xanthine, other than a carboxylic acid, increased the potency to inhibit the calmodulin-sensitive form of phosphodiesterase, if they were capable of donating electrons to the xanthine nucleus. Any substituent in the 8 position larger than H reduced the potency of the xanthines to inhibit the cAMP specific form of phosphodiesterase. Topographical maps of the active sites of the 2 forms of phosphodiesterase are presented.