title: Activities of caffeine, theophylline, and enprofylline analogs as tracheal relaxants.
abstract: A variety of xanthines cause tracheal relaxation, an activity predictive of antiasthmatic potential. Structural analogs of caffeine, theophylline, and enprofylline were examined for their abilities to relax carbamylcholine-stimulated guinea pig trachea in vitro. All caffeine analogs tested were more potent than caffeine (EC50 = 551 +/- 81 microM) except the 8-p-sulfophenyl analog. 1,3,7-Tripropylxanthine and 1,3,7-tripropargylxanthine were among the more potent analogs with EC50 values of 12 +/- 1.3 and 65 +/- 11 microM respectively. Increasing the polarity at the 1- or 3-position by substituting a propargyl group for an n-propyl group decreased relaxant activity, an effect not observed at the 7-position. The 8-cyclohexyl-, 8-cyclopentyl- and 8-phenyl-derivatives of caffeine were relatively potent (EC 50 = approximately 75 microM). The theophylline analog 1,3-di-n-propylxanthine was approximately two times more active than theophylline (EC50 = 162 +/- 17 microM). 3-Isobutyl-1-methylxanthine (EC50 = 7.1 +/- 1.8 microM) and 1-isoamyl-3-isobutylxanthine (EC50 = 37 +/- 4.2 microM) were among the most potent tracheal relaxants. The 8-substituted theophylline analogs were weak or inactive relaxants except for 8-cyclopentyl- and 8-cyclohexyltheophylline, which were more potent or as potent as theophylline. In contrast to enprofylline (EC50 = 56 +/- 9 microM), 8-substituted enprofylline analogs were weak or inactive as relaxants with the exception of the 8-cyclohexyl analog. The potency of xanthines as tracheal relaxants was unrelated to potency as adenosine receptor antagonists and may reflect activity as phosphodiesterase inhibitors.
authors.affiliation: Laboratory of Bioorganic Chemistry, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892.
authors.forename: L E
authors.initials: LE
authors.lastname: Brackett
authors.forename: M T
authors.initials: MT
authors.lastname: Shamim
authors.forename: J W
authors.initials: JW
authors.lastname: Daly
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D002110:Caffeine / Q000494:pharmacology*; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects*; D009126:Muscle Relaxation / Q000187:drug effects*; D009130:Muscle, Smooth / Q000187:drug effects*; D011983:Receptors, Purinergic / Q000187:drug effects; D013806:Theophylline / Q000494:pharmacology*; D014132:Trachea / Q000187:drug effects; D014970:Xanthines / Q000494:pharmacology*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D011983:Receptors, Purinergic; D014970:Xanthines; D002110:Caffeine; D013806:Theophylline; C034347:enprofylline