Examorelin (Hexarelin)

Examorelin (Hexarelin) is a synthetic hexapeptide agonist of the growth hormone secretagogue receptor (GHS-R) with an amino acid sequence of His-D-2-methyl-Trp-Ala-Trp-D-Phe-Lys-NH2^{[1, 2]}. Examorelin significantly and dose-dependently increases the plasma levels of growth hormone (GH) in animals and humans^[3]. Examorelin reached Phase II clinical trials for the treatment of growth hormone deficiency and congestive heart failure, but did not complete development and has never been marketed^[4].

In vitro, pretreatment of β-cell line MIN6 cells with Examorelin (1μM) for 2h significantly alleviated streptozotocin (STZ)-induced β-cell mitochondrial damage and increased superoxide dismutase activity, reduced the expression of intracellular caspase-3 and caspase-9, and reduced the ratio of pro-apoptotic protein Bax to anti-apoptotic protein Bcl-2^[5].

In vivo, oral treatment of mice with reperfusion ischemia (IR) model with Examorelin (0.3mg/kg/day) for 21 days improved left ventricular (LV) function, significantly reduced interstitial collagen, TGF-β1 expression and myofibroblast differentiation, and significantly reduced cardiac troponin-I and TNF-α levels^[6]. Subcutaneous treatment of adult albino Swiss mice with Examorelin (100, 200μg/kg/day) reduced the pregnancy index of male animals and the percentage of conception in female animals^[7].

References:
[1] Morton I, Morton I K, Hall J M, et al. Concise dictionary of pharmacological agents: properties and synonyms[M]. Springer Science & Business Media, 1999.
[2] Proulx C, Picard E, Boeglin D, et al. Azapeptide analogues of the growth hormone releasing peptide 6 as cluster of differentiation 36 receptor ligands with reduced affinity for the growth hormone secretagogue receptor 1a[J]. Journal of Medicinal Chemistry, 2012, 55(14): 6502-6511.
[3] Ishida J, Saitoh M, Ebner N, et al. Growth hormone secretagogues: history, mechanism of action, and clinical development[J]. JCSM rapid communications, 2020, 3(1): 25-37.
[4] Suckling K. Discontinued drugs in 2005: cardiovascular drugs[J]. Expert opinion on investigational drugs, 2006, 15(11): 1299-1308.
[5] Zhao Y, Zhang X, Chen J, et al. Hexarelin protects rodent pancreatic β-cells function from cytotoxic effects of streptozotocin involving mitochondrial signalling pathways in vivo and in vitro[J]. PLoS One, 2016, 11(2): e0149730.
[6] McDonald H, Peart J, Kurniawan N D, et al. Hexarelin targets neuroinflammatory pathways to preserve cardiac morphology and function in a mouse model of myocardial ischemia-reperfusion[J]. Biomedicine & Pharmacotherapy, 2020, 127: 110165.
[7] Puechagut P B, Martini A C, Stutz G, et al. Reproductive performance and fertility in male and female adult mice chronically treated with hexarelin[J]. Reproduction, Fertility and Development, 2012, 24(3): 451-460.

Examorelin (Hexarelin)是一种生长激素促分泌素受体（GHS-R）的合成六肽激动剂，氨基酸序列为His-D-2-methyl-Trp-Ala-Trp-D-Phe-Lys-NH2^{[1, 2]}。Examorelin显著地和剂量依赖性地增加动物和人类中生长激素（GH）的血浆水平^[3]。Examorelin达到了治疗生长激素缺乏症和充血性心力衰竭的II期临床试验，但没有完成开发，从未上市^[4]。

在体外，Examorelin（1μM）预处理β细胞系MIN6细胞2h，显著减轻了链脲佐菌素（STZ）诱导的β细胞线粒体损伤和超氧化物歧化酶活性升高，降低细胞内caspase-3、caspase-9的表达，降低了促凋亡蛋白Bax与抗凋亡蛋白Bcl-2的比例^[5]。

在体内，Examorelin（0.3mg/kg/day）通过口服治疗再灌注缺血（IR）模型小鼠21天，改善了小鼠左心室（LV）功能，显著减少了间质胶原、TGF-β1表达和肌成纤维细胞分化，显著降低了心肌肌钙蛋白-I和TNF-α水平^[6]。Examorelin（100, 200μg/kg/day）通过皮下注射处理成年白化病瑞士小鼠，降低了雄性动物的妊娠指数和雌性动物受孕百分比^[7]。