title: Original 2-alkylamino-6-halogenoquinazolin-4(3H)-ones and K(ATP) channel activity.
abstract: A series of 6-substituted 2-alkylaminoquinazolin-4(3H)-ones structurally related to 3-alkylamino-4H-pyrido[4,3-e]-1,2,4-thiadiazine 1,1-dioxides were synthesized and tested as putative K(ATP) channel openers on isolated pancreatic endocrine tissue as well as on isolated vascular, intestinal, and uterine smooth muscle. Most of the 6-halogeno-2-alkylaminoquinazolin-4(3H)-ones were found to inhibit insulin release from pancreatic B-cells and to exhibit vasorelaxant properties. In contrast to their pyridothiadiazine dioxide isosteres previously described as more active on the endocrine than on the smooth muscle tissue, quinazolinones cannot be considered as tissue selective compounds. Biological investigations, including measurements of (86)Rb, (45)Ca efflux from pancreatic islet cells and measurements of vasodilator potency in rat aortic rings exposed to 30 or 80 mM KCl in the presence or the absence of glibenclamide, were carried out with 6-chloro- and 6-iodo-3-isopropylaminoquinazolin-4(3H)-ones. Such experiments showed that, depending on the tissue, these new compounds did not always express the pharmacological profile of pure K(ATP) channel openers. Analyzed by X-ray crystallography, one example of quinazolinones appeared to adopt a double conformation. This only suggests a partial analogy between the 2-alkylaminoquinazolin-4(3H)-ones and the 3-alkylamino-4H-pyrido[4,3-e]-1,2,4-thiadiazine 1,1-dioxides. In conclusion, the newly synthesized quinazolinones interfere with insulin secretion and smooth muscle contractile activity. Most of the compounds lack tissue selectivity, and further investigations are required to fully elucidate their mechanism(s) of action.
authors.affiliation: Laboratoire de Chimie Pharmaceutique, Université de Liège, 1, Avenue de l'Hôpital, B-4000 Liège, Belgium.
authors.forename: F
authors.initials: F
authors.lastname: Somers
authors.forename: R
authors.initials: R
authors.lastname: Ouedraogo
authors.forename: M H
authors.initials: MH
authors.lastname: Antoine
authors.forename: P
authors.initials: P
authors.lastname: de Tullio
authors.forename: B
authors.initials: B
authors.lastname: Becker
authors.forename: J
authors.initials: J
authors.lastname: Fontaine
authors.forename: J
authors.initials: J
authors.lastname: Damas
authors.forename: L
authors.initials: L
authors.lastname: Dupont
authors.forename: B
authors.initials: B
authors.lastname: Rigo
authors.forename: J
authors.initials: J
authors.lastname: Delarge
authors.forename: P
authors.initials: P
authors.lastname: Lebrun
authors.forename: B
authors.initials: B
authors.lastname: Pirotte
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000502:physiology; D002118:Calcium; D018360:Crystallography, X-Ray; D005260:Female; D005905:Glyburide / Q000494:pharmacology; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D015221:Potassium Channels / Q000187:drug effects*; D011189:Potassium Chloride / Q000494:pharmacology; D011799:Quinazolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012413:Rubidium; D013329:Structure-Activity Relationship; D014590:Uterine Contraction / Q000187:drug effects; D014599:Uterus / Q000187:drug effects / Q000502:physiology
chemical_list: D007328:Insulin; D015221:Potassium Channels; D011799:Quinazolines; D011189:Potassium Chloride; D000255:Adenosine Triphosphate; D012413:Rubidium; D005905:Glyburide; D002118:Calcium