YIL 781是一种选择性的胃饥饿素受体（GHSR1a）拮抗剂，Ki值为17nM。
Cas No.:875258-85-8
Sample solution is provided at 25 µL, 10mM.
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YIL 781 is a selective ghrelin receptor (GHSR1a) antagonist with a Ki value of 17 nM[1]. YIL 781 inhibits ghrelin-induced calcium response and improves glucose homeostasis in rats[2]. Oral administration of YIL 781 to insulin-resistant diet-induced obesity (DIO) rats reduces blood glucose fluctuations[3].
In vitro, pretreatment of GHSR1a-expressing HEK-293T cells with YIL 781 (1µM) for 10min completely reversed ghrelin-mediated forskolin-induced decrease in cAMP levels (approximately 25%)[4]. Pretreatment of primary cultures of striatal neurons with YIL 781 (2µM) antagonized the GHSR1a signaling pathway induced by auxin-releasing peptide[5].
In vivo, intraperitoneal injection of YIL 781 (5mg/kg/day) in mice for 1 week significantly inhibited prostate enlargement induced by a high-fat diet and testosterone propionate (TP)[6]. YIL 781 (3mg/kg) reversed the effect of ulimorelin on renal sympathetic nerve activity (RSNA) in rats by intravenous injection[7].
References:
[1] Esler W P, Rudolph J, Claus T H, et al. Small-molecule ghrelin receptor antagonists improve glucose tolerance, suppress appetite, and promote weight loss[J]. Endocrinology, 2007, 148(11): 5175-5185.
[2] Perdonà E, Faggioni F, Buson A, et al. Pharmacological characterization of the ghrelin receptor antagonist, GSK1614343 in rat RC-4B/C cells natively expressing GHS type 1a receptors[J]. European journal of pharmacology, 2011, 650(1): 178-183.
[3] Sangiao-Alvarellos S, Cordido F. Effect of ghrelin on glucose‐insulin homeostasis: therapeutic implications[J]. International Journal of Peptides, 2010, 2010(1): 234709.
[4] Lillo J, Lillo A, Zafra D A, et al. Identification of the ghrelin and cannabinoid CB2 receptor heteromer functionality and marked upregulation in striatal neurons from offspring of mice under a high-fat diet[J]. International journal of molecular sciences, 2021, 22(16): 8928.
[5] Aguinaga D, Medrano M, Cordomí A, et al. Cocaine blocks effects of hunger hormone, ghrelin, via interaction with neuronal sigma-1 receptors[J]. Molecular neurobiology, 2019, 56(2): 1196-1210.
[6] Gu M, Liu C, Yang T Y, et al. High-fat diet induced gut microbiota alterations associating with Ghrelin/Jak2/Stat3 up-regulation to promote benign prostatic hyperplasia development[J]. Frontiers in cell and developmental biology, 2021, 9: 615928.
[7] Callaghan B, Kosari S, Pustovit R V, et al. Hypotensive effects of ghrelin receptor agonists mediated through a novel receptor[J]. British Journal of Pharmacology, 2014, 171(5): 1275-1286.
YIL 781是一种选择性的胃饥饿素受体（GHSR1a）拮抗剂，Ki值为17nM[1]。YIL 781能够抑制饥饿素诱导的钙反应，改善大鼠体内葡萄糖稳态[2]。口服YIL 781治疗胰岛素抵抗饮食诱导性肥胖（DIO）大鼠能够减少血糖波动[3]。
在体外，YIL 781（1µM）预处理表达GHSR1a的HEK-293T细胞10min，能够完全逆转由ghrelin介导的Forskolin诱导的cAMP水平降低（约25%）[4]。YIL 781（2µM）预处理纹状体神经元原代培养物，拮抗了生长素释放肽诱导的GHSR1a信号通路[5]。
在体内，YIL 781（5mg/kg/day）通过腹腔注射处理小鼠1周，显著抑制了高脂饮食和丙酸睾酮（TP）引起的前列腺增大[6]。YIL 781（3mg/kg）通过静脉注射处理大鼠，逆转了ulimorelin对大鼠肾交感神经活动（RSNA）的影响[7]。
| Cell experiment [1]: | |
Cell lines | HEK-293T cells |
Preparation Method | HEK-293T cells transfected with plasmids encoding for either GHSR1a (1.5μg) were pre-treated with selective antagonists for 10min, 1μM YIL 781-GHSR1a-, and subsequently treated with the selective agonists, 200nM ghrelin -GHSR1a-. cAMP levels after 0.5μM forskolin stimulation were detected by the Lance Ultra cAMP kit and the results were expressed in % respect to levels obtained upon forskolin stimulation. |
Reaction Conditions | 1µM; 10min |
Applications | In cells expressing the GHSR1a, ghrelin induced a 25% decrease of forskolin-induced cAMP levels that was completely counteracted by YIL 781 (1µM), the selective GHSR1a antagonist. |
| Animal experiment [2]: | |
Animal models | C57BL/6 mice |
Preparation Method | Mice were randomly divided into six groups with five mice in each group. (1) Normal group fed with a standard chow diet for 12 weeks and simultaneously injected with 0.9% normal saline daily for 2 weeks (Normal); (2) HFD group fed with HFD (45% kcal fat/17% kcal sucrose) for 12 weeks and simultaneously injected with 0.9% normal saline daily for 2 weeks; (3) Normal mice planted with gut microbiota from HFD mice group (Normal+HFDGM), received gut microbiota by intragastric administration once a week and fed with a standard chow diet for 12 weeks. The gut microbiota was isolated from fecal samples of HFD mice and cultured on agar media for 48 h. The gut microbiota from one HFD mouse was transplanted to a normal mouse. (4) High-fat diet BPH model group (BPH), fed HFD for 12 weeks and simultaneously received testosterone propionate (TP) (7.5mg/kg body weight, s.c.) daily for 2 weeks; (5) BPH with YIL 781 (BPH+YIL 781), BPH mice were injected with YIL 781, 5mg/kg body weight, i.p. daily for 1 week. Mice body weight was measured daily to adjust the dosage. Fasting blood glucose was detected and the feces were collected from mice after the last day and then the mice were sacrificed. The tissues of prostate gland were carefully harvested and weighed and then stored at −80℃ for further analysis. The prostatic index (PI) (prostate weight mg/100g body weight) was analyzed. |
Dosage form | 5mg/kg/day; 7 days; i.p. |
Applications | Ghrelin receptor antagonist YIL 781 showed little effect on ratio of Firmicutes to Bacteroidetes and blood ghrelin, however it significantly inhibits the prostate enlargement induced by HFD and testosterone propionate (TP). |
References: | |
| Cas No. | 875258-85-8 | SDF | |
| 化学名 | (S)-6-(4-fluorophenoxy)-3-((1-isopropylpiperidin-3-yl)methyl)-2-methylquinazolin-4(3H)-one hydrochloride | ||
| Canonical SMILES | FC1=CC=C(C=C1)OC2=CC=C3N=C(C)N(C(C3=C2)=O)C[C@@H]4CN(C(C)C)CCC4.Cl | ||
| 分子式 | C24H28FN3O2 | 分子量 | 409.5 |
| 溶解度 | <44.6mg/ml in DMSO; <44.6mg/ml in Water | 储存条件 | RT |
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| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.442 mL | 12.21 mL | 24.42 mL |
| 5 mM | 488.4 μL | 2.442 mL | 4.884 mL |
| 10 mM | 244.2 μL | 1.221 mL | 2.442 mL |
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| % DMSO % % Tween 80 % saline | ||||||||||
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