Influence of the alkylsulfonylamino substituent located at the 6-position of 2,2-dimethylchromans structurally related to cromakalim: from potassium channel openers to calcium entry blockers?

Abstract

The present study described the synthesis of original R/S-6-alkylsulfonylamino-3,4-dihydro-2,2-dimethyl-2H-1-benzopyrans bearing a 3- or 4-substituted phenylthiourea or phenylurea moiety at the 4-position. Their biological effects were evaluated both on insulin-secreting and smooth muscle cells and were compared to those of reference KATP channel activators such as (±)-cromakalim, diazoxide and previously synthesized cromakalim analogues. The study aimed at exploring the influence of the introduction of an alkylsulfonylamino substituent at the 6-position of 2,2-dimethylchromans in order to improve biological activity, tissue selectivity but also hydrophilicity of dihydrobenzopyran derivatives. Several compounds were found to be equipotent or even more potent than (±)-cromakalim and diazoxide at inhibiting the insulin releasing process. Most of the newly synthesized and more hydrophilic dihydrobenzopyrans also exhibited a marked vasorelaxant activity although they were less potent than (±)-cromakalim. Additional pharmacological and radioisotopic investigations suggested that R/S-N-3-chlorophenyl-N'-(3,4-dihydro-6-methylsulfonylamino-2,2-dimethyl-2H-1-benzopyran-4-yl)thiourea (21) did not act as a potassium channel opener but rather as a Ca(2+) entry blocker.

Keywords: ATP-sensitive potassium channels; Benzopyran derivatives; Cromakalim analogues; Insulin secretion; Potassium channel openers; Smooth muscle contractile activity.