PT - JOURNAL ARTICLE AU - N. D. Sonawane AU - Olga Zegarra-Moran AU - Wan Namkung AU - Luis J. V. Galietta AU - A. S. Verkman TI - α-Aminoazaheterocyclic-Methylglyoxal Adducts Do Not Inhibit Cystic Fibrosis Transmembrane Conductance Regulator Chloride Channel Activity AID - 10.1124/jpet.107.132357 DP - 2008 May 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 529--535 VI - 325 IP - 2 4099 - http://jpet.aspetjournals.org/content/325/2/529.short 4100 - http://jpet.aspetjournals.org/content/325/2/529.full SO - J Pharmacol Exp Ther2008 May 01; 325 AB - Inhibitors of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel have potential applications in the therapy of secretory diarrheas and polycystic kidney disease. In a recent study, several highly polar α-aminoazaheterocyclic-methylglyoxal adducts were reported to reversibly inhibit CFTR chloride channel activity with IC50 values in the low picomolar range (J Pharmacol Exp Ther322:1023–1035, 2007), more than 10,000-fold better than that of thiazolidinone and glycine hydrazide CFTR inhibitors previously identified by high-throughput screening. In this study, we resynthesized and evaluated the α-aminoazaheterocyclic-methylglyoxal adducts reported to have high CFTR inhibition potency (compounds 5, 7, and 8). We verified that the reported synthesis procedures produced the target compounds in high yield. However, we found that these compounds did not inhibit CFTR chloride channel function in multiple cell lines at up to 100 μM concentration, using three independent assays of CFTR function including short-circuit current analysis, whole-cell patch-clamp experiments, and yellow fluorescence protein-fluorescence quenching. As positive controls, approximately 100% of CFTR inhibition was found by thiazolidinone and glycine hydrazide CFTR inhibitors. Our data provide direct evidence against CFTR inhibition by α-aminoazaheterocyclic-methylglyoxal adducts. The American Society for Pharmacology and Experimental Therapeutics