Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, PR China; Structural Biology Center, Wenzhou Medical University, Wenzhou 325027, PR China.
Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, PR China.
Eur J Med Chem. 2017 Sep 29;138:1158-1169. doi: 10.1016/j.ejmech.2017.07.046. Epub 2017 Jul 24.
Glucagon has plenty of effects via a specific glucagon receptor(GCGR) like elevating the blood glucose, improving fatty acids metabolism, energy expenditure and increasing lipolysis in adipose tissue. The most important role of glucagon is to regulate the blood glucose, but the emergent possibilities of hyperglycaemia is exist. Glucagon could also slightly activate glucagon-like peptide-1 receptor(GLP-1R), which lead to blood glucose lowering effect. This study aims to erase the likelihood of hyperglycaemia and to remain the inherent catabolic effects through improving GLP-1R activation and deteriorating GCGR activation so as to lower the bodyweight and show diabetes-protective effects. Firstly, twelve cysteine modified GLP-1/GCGR dual agonists were synthesized (1-12). Then, the GLP-1R/GCGR mediated activation and biological activity in normal ICR mice were comprehensively performed. Compounds substituted by cysteine at positions 22, 23 and 25 in glucagon were observed to be better regulators of the body weight and blood glucose. To prolong the half-lives of derivatives, various fatty side chain maleimides were modified to optimal glucagon analogues. Laurate maleimide conjugate 4d was the most potent. Administration of 1000 nmol/kg 4d once every two days for a month normalized adiposity and glucose tolerance in diet-induced obese (DIO) mice. Improvements in plasma metabolic parameters including insulin, leptin, and adiponectin were observed. These studies suggest that compound 4d behaves well in lowering body weight and maintaining energy expenditure without a chance of hyperglycaemia, 4d has strong clinical potential as an efficient GLP-1/GCGR agonist in the prevention and treatment of obesity and dyslipidemia.
胰高血糖素通过特定的胰高血糖素受体 (GCGR) 发挥多种作用，如升高血糖、改善脂肪酸代谢、增加能量消耗和促进脂肪组织的脂肪分解。胰高血糖素最重要的作用是调节血糖，但也存在导致高血糖的潜在可能性。胰高血糖素还可以轻微激活胰高血糖素样肽-1 受体 (GLP-1R)，从而产生降低血糖的作用。本研究旨在通过提高 GLP-1R 的激活和降低 GCGR 的激活来消除高血糖的可能性，同时保持固有的分解代谢作用，从而降低体重并发挥糖尿病保护作用。首先，合成了 12 个半胱氨酸修饰的 GLP-1/GCGR 双重激动剂（1-12）。然后，在正常 ICR 小鼠中全面研究了 GLP-1R/GCGR 介导的激活和生物学活性。在胰高血糖素中，半胱氨酸取代 22、23 和 25 位的化合物被观察为更好的体重和血糖调节剂。为了延长衍生物的半衰期，各种脂肪酸侧链马来酰亚胺被修饰为最佳的胰高血糖素类似物。月桂酸马来酰亚胺缀合物 4d 是最有效的。每月两次给予 1000 nmol/kg 4d 一次，可使饮食诱导肥胖 (DIO) 小鼠的肥胖和葡萄糖耐量正常化。观察到血浆代谢参数包括胰岛素、瘦素和脂联素的改善。这些研究表明，化合物 4d 在降低体重和维持能量消耗方面表现良好，而不会导致高血糖，4d 作为一种有效的 GLP-1/GCGR 激动剂，具有很强的临床潜力，可用于预防和治疗肥胖症和血脂异常。
