α2-adrenoceptor is a G protein-coupled receptor (GPCR) associated with the Gi heterotrimeric G-protein. Besides, the α2-adrenoceptor not only inhibits the release of their neurotransmitters (autoreceptors) but can also regulate the exocytosis of several other neurotransmitters in the central and peripheral nervous system. Specificity, the α2-adrenergic receptor inhibits the release of norepinephrine (noradrenaline) in the form of negative feedback. Moreover, α2-adrenoceptor induces transient hypertension, followed by sustained hypotension (decrease in blood pressure). Meanwhile, the α2-adrenoceptor also decreases the release of acetylcholine and inhibits the norepinephrine system in the brain. Importantly, α2-adrenoceptor induces glucagon release from the pancreas. In addition, studies show that inhibiting the expression of α2-adrenoceptor caused blood glucose to decrease and increase blood pressure. So, It is important to find some α2-adrenoceptor antagonists for diabetes.
Midaglizole is a potent α2-adrenoceptor antagonist with hypoglycemic activity.
Midaglizole is a is a potent α2-adrenoceptor antagonist. Besides, Midaglizole exhibits 7.4 times higher affinity (pKi=6.28) toward α2-adrenoceptor than α1-adrenoceptor. In addition, Midaglizole stimulates insulin release with the EC50 values of 200 nM, and 24 µM for rat islets and MIN6 β-cell line, respectively. Moreover, Midaglizole inhibits KATP current with IC50 values of 3.8 μM and 4.4 uM for Kir6.2 and Kir6.2/SUR1, respectively.
Midaglizole also is a hypoglycemic agent. For example, Midaglizole (3, 30 mg/kg; i.v.) increases the blood pressure in 290-450 g, Male Wistar rats by 27 and 64 mmHg at 3, 30 mg/kg, respectively. Furthermore, Midaglizole (0.2, 1, 2 mg/kg; superior pancreaticoduodenal artery infusion) reduces blood glucose levels by stimulating insulin release from the pancreatic islets.
All in all, Midaglizole is a potent α2-adrenoceptor antagonist. Besides, Midaglizole increases blood pressure and reduces blood glucose levels in vivo.