title: In vitro and in vivo effects of new insulin releasing agents.
abstract: The present study aimed at characterizing in vitro and in vivo the effects of BM 208 (N-[4-(5-chloro-2-methoxybenzamidoethyl)benzenesulfonyl]-N'-cyano-N"-cyclohexylguanidine) and BM 225 (1-[4-(5-chloro-2-methoxybenzamidoethyl)benzene sulfonamido]-1-cyclohexylamino-2-nitroethylene); two new isosteres of the hypoglycemic sulfonylurea glibenclamide. In rat pancreatic islets perifused at close to normal (8.3mM) D-glucose concentration, both BM 208 and BM 225 (10 and 25 microM) increased 45Ca outflow and insulin release. The compounds did not affect the 45Ca outflow rate from islets exposed to Ca(2+)-free media. In single pancreatic islet cells loaded with the fluorescent Ca(2+) indicator fura-2 and incubated in the presence of 8.3mM glucose, BM 208 and BM 225 raised the [Ca(2+)](i). All these findings indicate that, in islet cells exposed to a physiological concentration of D-glucose, the secretory capacity of the new glibenclamide isosteres is related to a facilitation of Ca(2+) entry. The potency and duration of action of BM 225 was, however, more pronounced than that of BM 208. Successive additions of BM 208 provoked repeated increments in 45Ca outflow and insulin release, without evidence of tachyphylaxis. Lastly, intraperitoneal injection of BM 208 and BM 225 to fed rats lowered plasma glucose concentration in a dose-dependent manner. BM 225 was more potent and acting faster than BM 208. Our results indicate that appropriate structural modification can generate isosteres of glibenclamide with different features and activity profiles.
authors.affiliation: Laboratory of Pharmacology, Faculty of Medicine, Université Libre de Bruxelles, 808 route de Lennik, B-1070 Brussels, Belgium.
authors.forename: Quynh-Anh
authors.initials: QA
authors.lastname: Nguyen
authors.forename: Marie-Hélène
authors.initials: MH
authors.lastname: Antoine
authors.forename: Raogo
authors.initials: R
authors.lastname: Ouedraogo
authors.forename: Marcel
authors.initials: M
authors.lastname: Hermann
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Sergooris
authors.forename: Bernard
authors.initials: B
authors.lastname: Pirotte
authors.forename: Bernard
authors.initials: B
authors.lastname: Masereel
authors.forename: Philippe
authors.initials: P
authors.lastname: Lebrun
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002132:Calcium Radioisotopes; D005947:Glucose / Q000378:metabolism; D005905:Glyburide / Q000031:analogs & derivatives* / Q000494:pharmacology*; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism*; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
chemical_list: C118843:BM 208; C118844:BM 225; D001786:Blood Glucose; D002132:Calcium Radioisotopes; D007004:Hypoglycemic Agents; D007328:Insulin; D005947:Glucose; D005905:Glyburide; D002118:Calcium