Original 2-alkylamino-6-halogenoquinazolin-4(3H)-ones and K-ATP channel activity

A series of 6-substituted 2-alkylaminoquinazolin-4(3H)-ones structurally re lated to 3-alkyl-amino-4H-pyrido[4,3-e]-1,2,4-thiadiazine 1,1-dioxides were synthesized and tested as putative K-ATP channel openers on isolated pancr eatic endocrine tissue as well as on isolated vascular, intestinal, and ute rine smooth muscle. Most of the 6-halogeno-2-alkylaminoquinazolin-4(3H)ones were found to inhibit insulin release from pancreatic B-cells and to exhib it 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 selecti ve compounds. Biological investigations, including measurements of Rb-86, C a-45 efflux from pancreatic islet cells and measurements of vasodilator pot ency in rat aortic rings exposed to 30 or 80 mM KCI in the presence or the absence of glibenclamide, were carried out with 6-chloro- and 6-iodo-3-isop ropylaminoquinazolin-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)-o nes and the 3-alkylamino-4H-pyrido[4,3-e]-1,2,4-thiadiazine 1,1-dioxides. I n conclusion, the newly synthesized quinazolinones interfere with insulin s ecretion and smooth muscle contractile activity. Most of the compounds lack tissue selectivity, and further investigations are required to fully eluci date their mechanism(s) of action.