STRUCTURAL BASIS FOR SPECIFICITY AND POTENCY OF XANTHINE DERIVATIVES AS ACTIVATORS OF THE CFTR CHLORIDE CHANNEL

1 On the basis of their structure, we compared the ability of 35 xanth ine derivatives to activate the cystic fibrosis transmembrane conducta nce regulator (CFTR) chloride channel stably expressed in chinese hams ter ovary (CHO) cells using the cell-attached patch clamp and iodide e fflux techniques. 2 Activation of CFTR channels was obtained with 3-mo no, 1,3-di or 1,3,7-tri-substituted alkyl xanthine derivatives (enprof ylline, theophylline, aminophylline, IBMX, DPMX and pentoxifylline). B y contrast, xanthine derivatives substituted at the C8- or N9-position failed to open CFTR channels. 3 The CFTR chloride channel activity wa s blocked by glibenclamide (100 mu M) but not by DIDS (100 mu M). 4 Ac tivation of CFTR by xanthines was not mimicked by the calcium ionophor e A23187, adenosine, UTP, ATP or the specific phosphodiesterase inhibi tors rolipram, Ro 20-1724 and milrinone. In addition, we found no corr elation between the effect of xanthines on CFTR and on the cellular cy clic AMP or ATP levels. 5 We then synthesized a series of 3,7-dimethyl -1-alkyl xanthine derivatives; among them, 3,7-dimethyl-1-propyl xanth ine and 3,7-dimethyl-1-isobutyl xanthine both activated CFTR channels without increasing the intracellular cyclic AMP level, while the struc turally related 3,7-dimethyl-1-(2-propenyl) xanthine and 3,7-dimethyl- 1-(oxiranyl methyl) xanthine were inactive. 6 Our findings delineate a novel function for xanthine compounds and identify the molecular feat ures that enable xanthine activation of CFTR. These results may be use ful in the development of new molecules for studying the pharmacology of chloride channels.