| Abstract
| - The physiopathology of non-insulin-dependent diabetesmellitus is associated with a dysfunctionin the regulation of insulin secretion. Theα2-adrenoceptors have been reported to beinvolvedin this alteration, although α2-antagonists containing animidazoline ring may stimulate insulinsecretion independently of α2-adrenoceptor blockage.Recently, a new “imidazoline-bindingsite” involved in the control of K+-ATP channels in theB cell has been proposed. In the courseof searching for new antidiabetic agents,1-alkyl-2-(4‘,5‘-dihydro-1‘H-imidazol-2‘-yl)-4-benzylpiperazines,1-benzyl-2-(4‘,5‘-dihydro-1‘H-imidazol-2‘-yl)-4-alkylpiperazines,and 1-benzyl-2-(4‘,5‘-dihydro-1‘H-imidazol-2‘-yl)-4-benzylpiperazines havebeen designed and evaluated aspotential adrenoceptor antagonists. Pharmacological evaluation wasperformed in vivo usingglucose tolerance tests performed on a rat model of type II diabetesobtained by injection of alow dose (35 mg/kg) of streptozotocin (STZ). For some compounds,binding experiments wereperformed on α2 adrenoceptors and I1 andI2 imidazoline-binding sites. The biologicalandphysicochemical data have been combined with molecular modeling studiesto establishstructure−activity relationships. The most active compound was1-(2‘,4‘-dichlorobenzyl)-2-(4‘,5‘-dihydro-1‘H-imidazol-2‘-yl)-4-methylpiperazine(7f); intraperitoneal administration (100μmol/kg) of 7f strongly improved glucose tolerance in STZdiabetic rats. This effect seemed atleast partly mediated by a significant increase of insulin secretion.Other compounds of thesame family (7b, 16f, 23b) have alsoshown potent activity. We found no correlationbetweenin vivo antihyperglycemic properties and in vitroaffinities for α2-adrenoceptors or I1,and I2binding sites. These compounds can be considered asantihyperglycemic agents potentiallyuseful for treatment of type II diabetes and are currently undercomplementary investigation.
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