DIRECT ACTIVATION OF CYSTIC-FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR CHANNELS BY 8-CYCLOPENTYL-1,3-DIPROPYLXANTHINE (CPX) AND 1,3-DIALLYL-8-CYCLOHEXYLXANTHINE (DAX)

8-Cyclopentyl-1,3-dipropylxanthine (CPX) and 1,3-diallyl-8-cyclohexylx anthine (DAX) are xanthine adenosine antagonists which activate chlori de efflux from cells expressing either wild-type or mutant (Delta F508 ) cystic fibrosis transmembrane conductance regulator (CFTR). These dr ugs are active in extremely low concentrations, suggesting their possi ble therapeutic uses in treating cystic fibrosis. However, knowledge o f the mechanism of action of these compounds is lacking. We report her e that the same low concentrations of both CPX and DAX which activate chloride currents from cells also generate a profound activation of CF TR channels incorporated into planar lipid bilayers. The process of ac tivation involves a pronounced increase in the total conductive time o f the incorporated CFTR channels. The mechanism involves an increase i n the frequency and duration of channel opening events. Thus, activati on by these drugs of chloride efflux in cells very likely involves dir ect interaction of the drugs with the CFTR protein. We anticipate that this new information will contribute fundamentally to the rational de velopment of these and related compounds for cystic fibrosis therapy.