Insulin releasing action of 2-[2-(4,5-dihydro-1H-imadazol-2-yl)-1-phenylethyl] pyridine dihydrochloride sesquihydrate (DG-5128), a new, orally effective hypoglycaemic agent

Abstract

2-[2-(4,5-dihydro-1H-imidazol-2-yl)-1-phenyl\x=req-\ ethyl] pyridine dihydrochloride sesquihydrate is a new orally effective hypoglycaemic agent structurally unrelated to the known hypoglycaemics. DG-5128 was found to decrease blood glucose levels by stimulating insulin release, like the sulphonylurea hypoglycaemics. However, the study with the rat Langerhans islets in vitro indicated a great difference in mode of stimulation of insulin release between DG-5128 and a sulphonylurea hypoglycaemic, tolbutamide. DG-5128 significantly reversed \g=a\-adrenergic inhibition of the glucose-primed insulin release from the islets, while tolbutamide did not.From the comparison with the effects of phentolamine, yohimbine and prazosine, DG-5128 was strongly suggested to stimulate the glucose-primed insulin release through antagonizing at \g=a\2-adrenoreceptors on the B cells.In a previous report (Kameda et al., in press), we described the hypoglycaemic and antihyperglycaemic action of 2-[2-(4,5-dihydro-lH-imidazol-2-yl)-1-phenylethyl] pyridine dihydrochloride sesqui¬ hydrate in various animal species in¬ cluding mice, rats, dogs, monkeys and genetically diabetic mice of AyKK strain. Since DG-5128 hardly affected blood glucose levels in streptozotocin-induced diabetic rats, this compound was as¬ sumed to exert its hypoglycaemic action through stimulating insulin release, like the sulphonylurea hypoglycaemics. However, some difference was observed in hypo¬ glycaemic action between DG-5128 and tolbut¬ amide; the former was also effective in the geneti¬ cally diabetic AyKK mice, while the latter was not (Kameda et al., in press). In addition to the structural difference between DG-5128 and tolbut¬ amide, this difference in hypoglycaemic action between the 2 compounds has stimulated us to compare the mode of action of DG-5128 with that of tolbutamide. The present report describes the insulin releasing action of DG-5128 in rats in vivo and in vitro in comparison with that of tolbut¬ amide. Materials and MethodsDG-5128 was synthesized in this institute (Ishikawa 1980). The following chemicals were used: tolbutamide (Shinnihon Yakugyo Co., Tokyo), t-epinephrine bitartrate (Tokyo Kasei Kogyo Co., Tokyo), yohimbine hydrochloride (Nakarai Chemicals Co., Kyoto), phentolamine hydrochloride (Japan Ciba-Geigy Co., Takarazuka), prazosine hydrochloride (Taito-Pfizer Co., Tokyo), clonidine hydrochloride (C. H. Boehringer Sohn GmbH, Ingelheim), propranolol hydrochloride (Sumitomo Chemicals Co., Osaka), aprotinin (Trasylol, Bayer Co., Leverkusen), bovine serum albumin (Cohn Fraction V, Daiichi Pure Chemicals Co., Tokyo) and collagenase (Type I, Worthington Biochemical Corp., Freehold). Other chemicals used were of analytical grade.For the experiments in vivo, male Wistar:STD rats weighing 140-170 g were used after fasting overnight. DG-5128 or tolbutamide was dissolved in saline and injected into the tail vein at 2 ml/kg. Control rats received saline alone. For this purpose, tolbutamide was solubilized by the addition of a small amount of rat se...

.ALPHA.2-Adrenergic modulation of glucagon and insulin secretions in sheep.

“…Midaglizole administration stimulated insulin secretion and inhibited blood glucose level in rats (Kameda et al 1982; Koh et al 1987). It has been proposed that the enhanced insulin secretion was induced by the release from the adrenergic inhibition (Koh et al 1987).…”

“…Midaglizole is a selective a2-adrenergic antagonist (Kameda et al 1982;Muramatsu et al 1983). Midaglizole administration stimulated insulin secretion and inhibited blood glucose level in rats (Kameda et al 1982; Koh et al 1987).…”

Effects of midaglizole, a new hypoglycaemic drug on the electrophysiological properties of guinea‐pig papillary muscle

“…Hasegawa et al (1988) against a2-adrenoceptors (Kameda et al, 1982a,b;Yamanaka et al, 1984) or the low affinity state of x2-adrenoceptors (Yamanaka et al, 1985) and to reverse the a-adrenergic inhibition of insulin release from the pancreatic islet cells (Kameda et al, 1982b). This effect on insulin secretion from the pancreas which in turn reduces the serum glucose level has been recognized in basic (Kameda et al, 1981;1982a,b) and clinical studies (Kashiwagi et al, 1986;Kawazu et al, 1987a,b).…”

“…Midaglizole is a newly synthesized hypoglycaemic drug (Kameda et al, 1981;1982a) which antagonizes the a2-adrenoceptors (Yamanaka et al, 1984(Yamanaka et al, , 1985 of pancreatic f,-cells (Kameda et al, 1982b). The present experiments were performed in order to determine whether midaglizole inhibits the fast Na+ and slow Ca2+ channels in guinea-pig cardiac muscle and if so, whether the cardiac action of the drug represents a potential side-effect in its clinical use as a hypoglycaemic drug.…”

A Novel Adrenaline Derivative, AZ002, and Its Hypoglycemic Action in Yellow KK Mice

“…These were referred to as atypical /3-adrenoceptors and termed the 83-receptor. 13-Adrenoceptor agonists stimulate lipolysis and thermogenesis by selectively increasing the energy expenditure within brown adipose tissue, thereby providing a potential pharmacological treatment for obesity and NIDDM (10).…”