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?
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.
Laboratoire de Pharmacodynamie et de Thérapeutique, Université Libre de Bruxelles, Faculté de Médecine, 808 Route de Lennik, B-1070 Bruxelles, Belgium. Electronic address: xavier.florence@gmail.com.
Xavier
X
Florence
Centre de Recherches du Cyclotron, Université de Liège, 8 Allée du 6 Août, B-4000 Liège, Belgium.
Vincent
V
Desvaux
Laboratoire de Chimie Pharmaceutique, Centre Interfacultaire de Recherche du Médicament (C.I.R.M.), Université de Liège, C.H.U., 1 Avenue de l'Hôpital, B-4000 Liège, Belgium.
Eric
E
Goffin
Laboratoire de Chimie Pharmaceutique, Centre Interfacultaire de Recherche du Médicament (C.I.R.M.), Université de Liège, C.H.U., 1 Avenue de l'Hôpital, B-4000 Liège, Belgium.
Pascal
P
de Tullio
Laboratoire de Chimie Pharmaceutique, Centre Interfacultaire de Recherche du Médicament (C.I.R.M.), Université de Liège, C.H.U., 1 Avenue de l'Hôpital, B-4000 Liège, Belgium.
Bernard
B
Pirotte
Laboratoire de Pharmacodynamie et de Thérapeutique, Université Libre de Bruxelles, Faculté de Médecine, 808 Route de Lennik, B-1070 Bruxelles, Belgium.
Philippe
P
Lebrun
D000818:Animals; D001011:Aorta / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D001692:Biological Transport / Q000187:drug effects; D002118:Calcium / Q000378:metabolism*; D002839:Chromans / Q000737:chemistry*; D019806:Cromakalim / Q000737:chemistry* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism; D015640:Ion Channel Gating / Q000187:drug effects*; D009119:Muscle Contraction / Q000187:drug effects; D015221:Potassium Channels / Q000378:metabolism*; D011189:Potassium Chloride / Q000494:pharmacology; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013457:Sulfur Compounds / Q000737:chemistry*
D002839:Chromans; D007328:Insulin; D015221:Potassium Channels; D013457:Sulfur Compounds; D019806:Cromakalim; D011189:Potassium Chloride; D002118:Calcium
ATP-sensitive potassium channels; Benzopyran derivatives; Cromakalim analogues; Insulin secretion; Potassium channel openers; Smooth muscle contractile activity