Investigation of the role of i1- and i2-imidazoline receptors in the mechanіsm of the hypoglycemic action of n,n’-(ethane-1,2 dyyil)bis(quinoline- 2-carboxamide)

Abstract

The results of the investigation of the hypoglycemic action mechanism of N,N’-(ethane-1,2-dyyil)bis (quinoline-2-carboxamide) are presented. The substance was administered intragastrically in the dose of 11.64 mg/kg on the model of alloxan-induced diabetes mellitus in rats. It should be noted that the test compound in terms of the theory of pharmacophore can be considered as a dimer BU 224, but it is not its dimer in terms of organic chemistry. The information about the influence of the test compound on carbohydrate metabolism is limited. There are data that this compound has antitumor properties іn vitro due to enhanced apoptosis and activation of caspase-3. Proceeding from the chemical structure, the 2-substituted quinoline fragment is present in the structure of the known antagonist of imidazoline receptors I 2 such as 2-(4,5-dihydroimidazol-2-yl)quinoline hydrochloride, so it can be assumed that N,N’-(ethane-1,2-dyyil)bis(quinoline-2-carboxamide) has the ability to interfere with the mechanisms of the carbohydrate metabolism regulation. These results indicate that N,N’-(ethane-1,2-dyyil)bis(quinolin-2-carboxamide) has an expressed hypoglycemic effect in alloxan-induced diabetes mellitus reducing the blood glucose level by 71.50%. It is an agonist of imidazoline receptors of both types, and it has been proven by blockade with selective antagonists such as efaroxan and 2-(4,5-dihydroimidazol-2-yl)quinoline hydrochloride. On the background of I 1 -imidazoline receptors blocker efaroxan the glycemia decrease was 45.66% (p<0.05), and on the background of I2-imidazoline receptors blocker 2-(4,5-dihydroimidazol-2-yl)quinoline hydrochloride it was 54.01% (p<0.05). Diabetes mellitus (DM) type 2 is a chronic disease caused by decrease in sensitivity of the human tissues to insulin [1, 14]. The frequency of diabetes on average ranges from 1.5% to 3%; it is constantly increasing in the developed countries up to 5-7%, in Ukraine the value is twice lower – about 2.9%. There are about 200 million of diabetics in the world; almost 90% of them suffer from type 2 diabetes [5, 15]. The urgency of DM problem is caused by a signifi cant prevalence of the disease, severity of complications, disability and early mortality. Microangiopathies and neuropathies are the basis of diabetic complications. The patients with diabetes have a significant risk of athero sclerosis and coronary heart disease. More than 40% of amputations of lower limbs are a consequence of the diabetic foot syndrome. Diabetes is also the most common cause of blindness in humans [12, 17]. All mentioned above stipulates the necessity of development and research of new effective drugs with the hypoglycemic effect allowing to prevent development of the severe course of DM. The mechanism of action of different antidiabetic drugs consists of a several links. There are data on the role of imidazoline receptors in implementation of the hypoglycemic effect, in particular for biguanides derivatives such as metformin [7]. Imidazoline receptors are the independent type of receptors represented by two subtypes: 11 and 12. Subtypes are distinguished according to the specific ligands that bind with them. Imidazoline receptors mediate the following effects: increase of glucose-dependent insulin release and transport of glucose into the cells and, as a result, decrease of hyperglycemia, improvement of the