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Activators of the CFTR Cl[sup -] channel may be useful for therapy of cystic fibrosis. Short-circuit current (I[sub sc]) measurements were done on human bronchial epithelial cells to characterize the best flavone and benzimidazolone CFTR activators identified by lead-based combinatorial synthesis and high-throughput screening. The 7,8-benzoflavone UC[sub CF]-029 was a potent activator of Cl[sup -] transport, with activating potency (<1 µM) being much better than other flavones, such as apigenin. The benzimidazolone UCCF-853 gave similar I[sub sc] but with lower potency (5-20 µM). In combination, the effect induced by maximal UCCF-029 and UCCF-853 was 50-80% greater than that of either compound alone. The apparent activating potencies (K[sub d]) of UCCF-029, UCCF-853, and apigenin increased strongly with increasing basal CFTR activity: for example, K[sub d] for activation by UCCF029 decreased from >5 to <0.4 µM with increasing basal I[sub sc] from ∼4 µA/cm² to ∼12 µA/cm². This dependence was confirmed in permeabilized Fischer rat thyroid cells stably expressing CFTR. Our results demonstrate efficacy of novel CFTR activators in bronchial epithelia and provide evidence that activating potency depends on basal CFTR activity. [ABSTRACT FROM AUTHOR]