Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, Australia (M.M.F., P.K., T.T.T., G.M., C.A.H., P.Z., S.G.B.F., D.W., P.M.S.); Research and Development, Novo Nordisk, Denmark (T.K., T.R.C.); and ARC Centre for Cryo-electron Microscopy of Membrane Proteins, Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, Australia (D.W., P.M.S.).
Drug Discovery Biology Theme, Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, Australia (M.M.F., P.K., T.T.T., G.M., C.A.H., P.Z., S.G.B.F., D.W., P.M.S.); Research and Development, Novo Nordisk, Denmark (T.K., T.R.C.); and ARC Centre for Cryo-electron Microscopy of Membrane Proteins, Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, Australia (D.W., P.M.S.)
J Pharmacol Exp Ther. 2021 Jun;377(3):417-440. doi: 10.1124/jpet.121.000567. Epub 2021 Mar 16.
Obesity and associated comorbidities are a major health burden, and novel therapeutics to help treat obesity are urgently needed. There is increasing evidence that targeting the amylin receptors (AMYRs), heterodimers of the calcitonin G protein-coupled receptor (CTR) and receptor activity-modifying proteins, improves weight control and has the potential to act additively with other treatments such as glucagon-like peptide-1 receptor agonists. Recent data indicate that AMYR agonists, which can also independently activate the CTR, may have improved efficacy for treating obesity, even though selective activation of CTRs is not efficacious. AM833 (cagrilintide) is a novel lipidated amylin analog that is undergoing clinical trials as a nonselective AMYR and CTR agonist. In the current study, we have investigated the pharmacology of AM833 across 25 endpoints and compared this peptide with AMYR selective and nonselective lipidated analogs (AM1213 and AM1784), and the clinically used peptide agonists pramlintide (AMYR selective) and salmon CT (nonselective). We also profiled human CT and rat amylin as prototypical selective agonists of CTR and AMYRs, respectively. Our results demonstrate that AM833 has a unique pharmacological profile across diverse measures of receptor binding, activation, and regulation. SIGNIFICANCE STATEMENT: AM833 is a novel nonselective agonist of calcitonin family receptors that has demonstrated efficacy for the treatment of obesity in phase 2 clinical trials. This study demonstrates that AM833 has a unique pharmacological profile across diverse measures of receptor binding, activation, and regulation when compared with other selective and nonselective calcitonin receptor and amylin receptor agonists. The present data provide mechanistic insight into the actions of AM833.
肥胖症及其相关合并症是一个重大的健康负担，迫切需要新型治疗方法来帮助治疗肥胖症。越来越多的证据表明，靶向淀粉样肽受体（AMYRs），即降钙素基因相关肽（CTR）和受体活性修饰蛋白的异二聚体，可改善体重控制，并有可能与其他治疗方法（如胰高血糖素样肽-1 受体激动剂）联合发挥作用。最近的数据表明，AMYR 激动剂（也可以独立激活 CTR）可能对治疗肥胖症具有更好的疗效，尽管选择性激活 CTR 并不有效。AM833（cagrilintide）是一种新型的脂质化淀粉样肽类似物，目前正在作为非选择性 AMYR 和 CTR 激动剂进行临床试验。在本研究中，我们研究了 AM833 在 25 个终点的药理学特性，并将该肽与 AMYR 选择性和非选择性脂质化类似物（AM1213 和 AM1784）以及临床使用的肽激动剂普兰林肽（AMYR 选择性）和鲑鱼 CT（非选择性）进行了比较。我们还对人 CT 和大鼠淀粉样肽分别作为 CTR 和 AMYR 的典型选择性激动剂进行了分析。我们的研究结果表明，AM833 在受体结合、激活和调节的多种测量中具有独特的药理学特征。
AM833 是一种新型的降钙素家族受体非选择性激动剂，在 2 期临床试验中已被证明对肥胖症的治疗有效。与其他选择性和非选择性降钙素受体和淀粉样肽受体激动剂相比，本研究表明 AM833 在受体结合、激活和调节的多种测量中具有独特的药理学特征。本研究数据提供了 AM833 作用机制的深入了解。
