Asymmetric 4-aryl-1,4-dihydropyridines potentiate mutant cystic fibrosis transmembrane conductance regulator (CFTR).

Some of the genetic mutations that cause cystic fibrosis (CF) impair the gating of the cystic fibrosis transmembrane conductance regulator (CFTR) Cl(-) ion channel. This defect can be corrected with pharmacological tools (potentiators) that belong to various chemical families, including the 1,4-dihydropyridines (DHPs). A small set of asymmetric 4-aryl-DHPs was synthesized, and each racemic couple was tested in a functional assay carried out on cells expressing the G1349D, ΔF508, and G551D mutants. The most active racemates were subjected to chiral separation by HPLC, and the pure enantiomers were tested to evaluate any gains in activity. Although three enantiomers demonstrated high potency (K(d) values less than 0.09, 0.1, and 0.5 μM in G1349D, ΔF508, and G551D, respectively), in general, the screening of pure enantiomers did not produce a great diversity in potency values. It is probable that the degree of DHP asymmetry considered in our analysis is still insufficient with respect to that allowed in a putative DHP binding site in CFTR, so that the site could equally accommodate both enantiomers.