Glucagon-like peptide-1 (GLP-1) receptor

胰高血糖素样肽-1（GLP-1）作为2型糖尿病的常规治疗因其生物半衰期短而受到破坏。降解的一个原因是其N端HAE序列被二肽基肽酶IV（DPP IV）切割。为了预防DPP IV，我们研究了GLP-1类似物的生物活性，其中6-氨基己酸（Aha）插入组氨酸和丙氨酸之间的位置7和8。我们将这种新化合物GLP-1 Aha（8）的生物活性与之前描述的GLP-1 8-甘氨酸（GLP-1 Gly（8））类似物进行了比较。GLP-1 Aha（8）（10 nM）在刺激RIN 1046-38细胞中的胰岛素分泌方面与GLP-1（10 nM）等效。与GLP-1 Gly（8）一样，GLP-1 Aha（8）对表达人GLP-1受体的完整中国仓鼠卵巢（CHO）细胞（CHO/GLP-1R细胞）中GLP-1受体结合亲和力降低（IC（50）：GLP-1，3.7+/-0.2 nM；GLP-1 Gly（8），41+/-9nM；GLP-1 Aha（8）、22+/-7nM）。GLP-1 Aha（8）在低至0.5nM的浓度下也显示出刺激细胞内cAMP产生比基础水平高4倍。然而，与GLP-1和GLP-1 Gly（8）相比，它表现出更高的ED（50）（ED（50:GLP-1，0.036+/-0.002 nM，GLP-1 Gly8，0.13+/-0.02 nM，GL-1 Aha 8，0.58+/-0.03 nM）。还检查了一系列D-氨基酸取代的GLP-1化合物，以评估GLP-1分子中存在的推定肽酶敏感切割位点的重要性。它们对GLP-1受体的结合亲和力较差，且这些化合物均未刺激CHO/GLP-1R细胞内cAMP的产生或RIN 1046-38细胞的胰岛素分泌[4]。

观察到24小时平均加权葡萄糖[曲线下面积（0-24h）]的显著剂量依赖性降低，32 mg队列中安慰剂调整的最小二乘平均差值分别为-34.8和-56.4 mg/dl[95%置信区间（-54.1，-15.5）和（-82.2，-30.5）]，第2天和第9天。安慰剂调整后的空腹血糖在第2天和第9天分别下降了-26.7和-50.7 mg/dl[95%置信区间（-46.3，-7.06）和（-75.4，-26.0）]。餐后血糖也降低了。在albiglutide队列中未检测到低血糖事件。最常见的不良事件头痛和恶心的频率和严重程度与安慰剂对照组相当。Albiglutide的半衰期在6至7天之间。Albiglutid的药代动力学或药效学不受注射部位的影响。 结论：Albiglutide改善了2型糖尿病患者的空腹血糖和餐后血糖，具有良好的安全性。Albiglutide的半衰期较长，可以每周给药一次或减少给药频率[1]

---

对禁食的Zucker（fa/fa）大鼠皮下注射GLP-1 Aha（8）（24 nmol/kg）（平均血糖，195+/-32 mg/dl），将血糖水平降至最低值109+/-3 mg/dl，并在8小时内保持显著较低水平。与DPP IV（37℃，2小时）一起孵育的GLP-1 Aha（8）的基质辅助线性解吸电离飞行时间质谱没有显示出N端降解产物。综上所述，这些结果表明，在GLP-1的7位后插入Aha会产生有效、长效的GLP-1类似物，这可能有助于治疗2型糖尿病[4]。

Objectives: The objectives were to investigate pharmacodynamics, pharmacokinetics, safety, and tolerability of albiglutide in type 2 diabetes subjects. Methods: In a single-blind dose-escalation study, 54 subjects were randomized to receive placebo or 9-, 16-, or 32-mg albiglutide on d 1 and 8. In a complementary study, 46 subjects were randomized to a single dose (16 or 64 mg) of albiglutide to the arm, leg, or abdomen.[1]

[1]. Pharmacodynamics, pharmacokinetics, safety, and tolerability of albiglutide, a long-acting glucagon-like peptide-1 mimetic, in patients with type 2 diabetes. J Clin Endocrinol Metab. 2008 Dec;93(12):4810-7.

[2]. Albiglutide: a review of its use in patients with type 2 diabetes mellitus. Drugs. 2015 Apr;75(6):651-63.

[3]. Albiglutide: a new GLP-1 receptor agonist for the treatment of type 2 diabetes. Ann Pharmacother. 2014 Nov;48(11):1494-501.

[4]. Insertion of an N-terminal 6-aminohexanoic acid after the 7 amino acid position of glucagon-like peptide-1 produces a long-acting hypoglycemic agent. Endocrinology. 2001 Oct;142(10):4462-8.

Albiglutide (Eperzan(®), Tanzeum(®)), administered subcutaneously once weekly, is a glucagon-like peptide (GLP)-1 receptor agonist approved for the treatment of type 2 diabetes mellitus in several countries. Albiglutide has a longer half-life than native GLP-1, since it is resistant to degradation by the dipeptidyl peptidase-4 enzyme. As an incretin mimetic, albiglutide enhances glucose-dependent insulin secretion, suppresses inappropriate glucagon secretion, delays gastric emptying and reduces food intake. Several phase III clinical trials have demonstrated the efficacy of albiglutide in terms of improving glycaemic control in patients with inadequately controlled type 2 diabetes, including its use as monotherapy or add-on therapy to other antidiabetic agents (e.g. metformin, sulfonylureas, thiazolidinediones and insulins). In addition to improving glycaemic control, albiglutide had beneficial effects on bodyweight. These improvements in glycaemic control and reductions in bodyweight were maintained during long-term treatment (up to 3 years). Albiglutide was generally well tolerated in clinical trials, with mild to moderate gastrointestinal adverse events seen most commonly. Albiglutide has a convenient once-weekly administration regimen and a low risk of hypoglycaemia (except when used in combination with agents that may be associated with hypoglycaemia, such as sulfonylureas or insulin). Thus, albiglutide is an effective and generally well tolerated treatment option for patients with inadequately controlled type 2 diabetes.[2]

---

Objective: To review the pharmacology, pharmacokinetics, safety, and efficacy of albiglutide, a glucagon-like peptide-1 receptor agonist (GLP-1 RA) in type 2 diabetes (T2D). Data sources: A MEDLINE search (1950-June 2014) was conducted using the keyword albiglutide. References were reviewed to identify additional sources. Study selection and data extraction: Articles evaluating pharmacokinetics, pharmacodynamics, safety, or efficacy of albiglutide were included. Data synthesis: Albiglutide is a long-acting GLP-1 RA that lowers glycosylated hemoglobin (A1C) and reduces weight by stimulating glucose-dependent insulin secretion, suppressing glucagon secretion, delaying gastric emptying, and promoting satiety. Albiglutide has a long half-life as a result of resistance to degradation by dipeptidyl peptidase-4 and fusion to albumin, thus allowing once-weekly dosing. Albiglutide has been studied as monotherapy and add-on therapy to metformin, sulfonylureas, thiazolidinediones, insulin glargine, and varying combinations of these agents. Clinical studies have shown albiglutide to be superior to placebo, sitagliptin, and glimepiride and noninferior to insulin glargine and insulin lispro at reducing A1C in T2D patients, with A1C changes from baseline ranging from -0.55% to -0.9%. Noninferiority was not achieved when compared to liraglutide and pioglitazone. Weight changes ranged from +0.28 to -1.21 kg. The most common side effects are upper-respiratory-tract infections, diarrhea, nausea, and injection-site reactions. Conclusion: Albiglutide is the fourth GLP-1 RA approved in the United States. Advantages include once-weekly dosing and fewer gastrointestinal side effects compared with liraglutide, but it is less effective at reducing A1C and weight compared to liraglutide. It has not been compared head to head with other GLP-1 RAs. [3]

224638-84-0

Albiglutide fragment TFA;Albiglutide;782500-75-8

His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp-Leu-Val-Lys-Gly-Arg-NH2

HGEGTFTSDVSSYLEGQAAKEFIAWLVKGR-NH2

Typically exists as solid at room temperature

8-Glycine-36-L-argininamide-7-36-Glucagon-like peptide 1 (Octodon degus); 224638-84-0; H-His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp-Leu-Val-Lys-Gly-Arg-NH2

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: 如何溶解多肽产品？请参考本产品网页右上角“产品说明书”文件，第4页。

---

注意: 如下所列的是一些常用的体内动物实验溶解配方，主要用于溶解难溶或不溶于水的产品（水溶度<1 mg/mL）。 建议您先取少量样品进行尝试，如该配方可行，再根据实验需求增加样品量。

---

注射用配方1: DMSO : Tween 80： Saline = 10 : 5 : 85 (如： 100 μL DMSO → 50 μL Tween 80 → 850 μL Saline)
*生理盐水/Saline的制备：将0.9g氯化钠/NaCl溶解在100 mL ddH ₂ O中，得到澄清溶液。
注射用配方 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL DMSO → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline)
注射用配方 3: DMSO : Corn oil = 10 : 90 (如： 100 μL DMSO → 900 μL Corn oil)
示例: 以注射用配方 3 (DMSO : Corn oil = 10 : 90) 为例说明, 如果要配制 1 mL 2.5 mg/mL的工作液, 您可以取 100 μL 25 mg/mL 澄清的 DMSO 储备液，加到 900 μL Corn oil/玉米油中, 混合均匀。

View More

注射用配方 4: DMSO : 20% SBE-β-CD in Saline = 10 : 90 [如：100 μL DMSO → 900 μL (20% SBE-β-CD in Saline)]
*20% SBE-β-CD in Saline的制备（4°C，储存1周）：将2g SBE-β-CD (磺丁基-β-环糊精) 溶解于10mL生理盐水中，得到澄清溶液。
注射用配方 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (如： 500 μL 2-Hydroxypropyl-β-cyclodextrin (羟丙基环胡精)→ 500 μL Saline)
注射用配方 6: DMSO : PEG300 : Castor oil : Saline = 5 : 10 : 20 : 65 (如： 50 μL DMSO → 100 μL PEG300 → 200 μL Castor oil → 650 μL Saline)
注射用配方 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (如： 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
注射用配方 8: 溶解于Cremophor/Ethanol (50 : 50), 然后用生理盐水稀释。
注射用配方 9: EtOH : Corn oil = 10 : 90 (如： 100 μL EtOH → 900 μL Corn oil)
注射用配方 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL EtOH → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline)

---

口服配方 1: 悬浮于0.5% CMC Na (羧甲基纤维素钠)
口服配方 2: 悬浮于0.5% Carboxymethyl cellulose (羧甲基纤维素)
示例: 以口服配方 1 (悬浮于 0.5% CMC Na)为例说明, 如果要配制 100 mL 2.5 mg/mL 的工作液, 您可以先取0.5g CMC Na并将其溶解于100mL ddH2O中，得到0.5%CMC-Na澄清溶液；然后将250 mg待测化合物加到100 mL前述 0.5%CMC Na溶液中，得到悬浮液。

View More

口服配方 3: 溶解于 PEG400 (聚乙二醇400)
口服配方 4: 悬浮于0.2% Carboxymethyl cellulose (羧甲基纤维素)
口服配方 5: 溶解于0.25% Tween 80 and 0.5% Carboxymethyl cellulose (羧甲基纤维素)
口服配方 6: 做成粉末与食物混合

---

注意: 以上为较为常见方法，仅供参考， InvivoChem并未独立验证这些配方的准确性。具体溶剂的选择首先应参照文献已报道溶解方法、配方或剂型，对于某些尚未有文献报道溶解方法的化合物，需通过前期实验来确定（建议先取少量样品进行尝试），包括产品的溶解情况、梯度设置、动物的耐受性等。

---

请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。