title: Structure-activity relationship of xanthines and skeletal muscle ryanodine receptor/Ca2+ release channel.
abstract: Caffeine (1,3,7-trimethylxanthine) in the millimolar range is known to activate the skeletal muscle Ca2+ release channel (ryanodine receptor). Xanthine analogs substituted in the 1, 3, 7, 8 and 9 positions were tested for their capacity to increase [3H]ryanodine binding to skeletal muscle sarcoplasmic reticulum vesicles enriched in Ca2+ release activity and ryanodine receptor content. Of the 30 xanthines tested, 9 were more effective than caffeine in increasing [3H]ryanodine binding. The 7-methyl group of caffeine was most important for activating the ryanodine receptor, followed by the methyl groups in the 1 and 3 positions. An increase in hydrophobicity of the side chains in positions 7, 1 and 3 enhanced the ability of xanthines to activate the ryanodine receptor. Substitutions in positions 8 and 9 were without effect or were inhibitory. These results should help in developing xanthines specific for the sarcoplasmic reticulum Ca2+ release channel.
authors.affiliation: Department of Physiology, University of North Carolina, Chapel Hill 27599-7260, USA.
authors.forename: W
authors.initials: W
authors.lastname: Liu
authors.forename: G
authors.initials: G
authors.lastname: Meissner
mesh_terms: D000255:Adenosine Triphosphate / Q000031:analogs & derivatives / Q000378:metabolism; D000818:Animals; D001667:Binding, Competitive; D002110:Caffeine / Q000378:metabolism / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000187:drug effects* / Q000378:metabolism; D002148:Calmodulin-Binding Proteins / Q000187:drug effects / Q000378:metabolism*; D000697:Central Nervous System Stimulants / Q000378:metabolism / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D009124:Muscle Proteins / Q000187:drug effects* / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism; D011817:Rabbits; D012433:Ryanodine / Q000378:metabolism; D019837:Ryanodine Receptor Calcium Release Channel; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D013329:Structure-Activity Relationship; D014970:Xanthines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D015220:Calcium Channels; D002148:Calmodulin-Binding Proteins; D000697:Central Nervous System Stimulants; D009124:Muscle Proteins; D019837:Ryanodine Receptor Calcium Release Channel; D014970:Xanthines; D012433:Ryanodine; C005147:5'-adenylyl (beta,gamma-methylene)diphosphonate; D002110:Caffeine; D000255:Adenosine Triphosphate; C002630:alpha,beta-methyleneadenosine 5'-triphosphate; D002118:Calcium