Binding studies and GRIND/ALMOND-based 3D QSAR analysis of benzothiazine type KATP-channel openers

Abstract For seventeen 1,4-benzothiazine potassium channel openers, we performed binding studies in rat aortic smooth muscle cells and cardiomyocytes, compared their binding affinities with published relaxation data, and derived 3D-QSAR models using GRIND/ALMOND descriptors. Binding affinities in smooth muscle cells range from a p K D of 4.76 for compound 3e to 9.10 for compound 4c . Comparison of data for smooth muscle relaxation and binding shows preferentially higher pEC 50 s for the former. In cardiomyocytes, p K D values range from 4.21 for 3e to 8.16 for 4c . 3D-QSAR analysis resulted in PLS models of two latent variables for all three activities with determination coefficients of 0.97 (smooth muscle relaxation) and 0.94 (smooth muscle cells- and cardiomyocytes-binding). Internal validation yielded q 2 values of 0.69, 0.66, and 0.64. The carbonyl on the N-4 substituent, the hydrogen bond acceptor at C-6, the five-membered ring at N-4, and the gem -dimethyls mainly guide strong binding and strong smooth muscle relaxation.