更新于：2024-11-01

GLP-1R x CCKA

更新于：2024-11-01

基本信息

关联

项与 GLP-1R x CCKA 相关的药物

AC-3174/AC170222

靶点

CCKA x GLP-1R

作用机制

CCKA激动剂 [+1]

在研机构

MedImmune LLC [+1]

原研机构

MedImmune Ltd.

在研适应症

糖尿病 [+1]

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 GLP-1R x CCKA 相关的临床结果

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100 项与 GLP-1R x CCKA 相关的转化医学

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0 项与 GLP-1R x CCKA 相关的专利（医药）

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项与 GLP-1R x CCKA 相关的文献（医药）

2024-08-01·European Journal of Pharmaceutical Sciences

Discovery of novel glucagon-like peptide 1/cholecystokinin 1 receptor dual agonists

Article

作者: Qian, Long ; Binbin, Gong ; Ting, Wang ; Lidan, Sun ; Guoqiang, Hu ; Xiaoyi, Sun ; Chenxu, Zhou

The combined use of gastrointestinal hormones for treating metabolic diseases is gaining increasing attention. The potential of developing novel dual agonists targeting both cholecystokinin 1 (CCK-1) receptor and glucagon-like peptide 1 (GLP-1) receptor to improve the treatment of type 2 diabetes and obesity have not been fully explored. In this investigation, we reported a series of novel GLP-1/CCK-1 receptor co-agonists constructed by linking the C-terminus of a GLP-1 receptor agonist (bullfrog GLP-1) to the N-terminus of a CCK-1 receptor selective agonist NN9056. In comprehensive in vitro assays, these co-agonists exhibited complete agonistic potency on GLP-1 and CCK-1 receptor. Remarkably, 1f displayed superior hypoglycemic and insulinotropic effects when compared to NN9056 and semaglutide. Evaluation in Kunming and diet-induced obesity (DIO) mice unveiled significant acute and enduring hypoglycemic effects of 1f. Administration of 1f to DIO mice resulted in substantial weight loss, normalized lipid metabolism, and enhanced glucose regulation. These preclinical observations strongly advocate for the therapeutic potential CCK-1 and GLP-1 pathways could be harnessed in a single fusion peptide, yielding a promising combination therapy strategy for treating metabolic disorders.

2024-01-01·FEBS Open Bio

Functional engineering of human iPSC‐derived parasympathetic neurons enhances responsiveness to gastrointestinal hormones

Article

作者: Miyamoto, Yasuhisa ; Nihashi, Yuma ; Yamashita, Azusa ; Akagi, Yuka ; Yoshida, Risa ; Kida, Yasuyuki S ; Takayama, Yuzo

Food‐derived biological signals are transmitted to the brain via peripheral nerves through the paracrine activity of gastrointestinal (GI) hormones. The signal transduction circuit of the brain–gut axis has been analyzed in animals; however, species‐related differences and animal welfare concerns necessitate investigation using in vitro human experimental models. Here, we focused on the receptors of five GI hormones (CCK, GLP1, GLP2, PYY, and serotonin (5‐HT)), and established human induced pluripotent stem cell (iPSC) lines that functionally expressed each receptor. Compared to the original iPSCs, iPSCs expressing one of the receptors did not show any differences in global mRNA expression, genomic stability, or differentiation capacities of the three germ layers. We induced parasympathetic neurons from these established iPSC lines to assess vagus nerve activity. We generated GI hormone receptor‐expressing neurons (CCKAR, GLP1R, and NPY2R‐neuron) and tested their responsiveness to each ligand using Ca2+ imaging and microelectrode array recording. GI hormone receptor‐expressing neurons (GLP2R and HTR3A) were generated directly by gene induction into iPSC‐derived peripheral nerve progenitors. These receptor‐expressing neurons promise to contribute to a better understanding of how the body responds to GI hormones via the brain–gut axis, aid in drug development, and offer an alternative to animal studies.

1998-01-01·Endocrinology2区 · 医学

Glucagon-Like Peptide-1-(7–36) Amide and Peptide YY Mediate Intraduodenal Fat-Induced Inhibition of Acid Secretion in Dogs*

2区 · 医学

Article

作者: Greenberg, Gordon R. ; Fung, Leslie C. ; Chisholm, Connie

AbstractIntraduodenal fat inhibits gastric acid secretion via the release of one or more hormonal enterogastrones thought to arise from ileo-colonic mucosa. This study determined whether glucagon-like peptide-1 (GLP-1)-(7–36) amide and peptide YY (PYY), colocalized in L cells found in the ileum, mediate intraduodenal fat-induced inhibition of stimulated gastric acid, and evaluated the influence of cholecystokinin-A (CCK-A) receptor activation. Gastric acid secretion in response to duodenal perfusions of 8% peptone was measured in conscious dogs with gastric and duodenal cannulas. Intraduodenal administration of a 10% fat emulsion suppressed gastric acid secretion by 72 ± 4% (P < 0.001) and increased plasma levels of GLP-1 and PYY by 44 ± 5 and 46 ± 4 fmol/ml, respectively (both P < 0.01). Pretreatment with the CCK-A receptor antagonist MK-329 completely reversed the inhibition of gastric acid by fat, suppressed rises of plasma GLP-1 (maximum change, 23 ± 4 fmol/ml), and reduced plasma PYY responses to baseline. Intravenous infusions of 50 pmol/kg·h GLP-1 or PYY, which reproduced plasma elevations after intraduodenal fat, inhibited gastric acid secretion by 66 ± 5% and 51 ± 6%, respectively (both P < 0.01); coinfusions of GLP-1 and PYY abolished gastric acid secretion (P < 0.001) without influencing plasma gastrin or somatostatin. Pretreatment with 1500 pmol/kg·h of the GLP-1 antagonist exendin-(9–39) amide did not alter the magnitude of inhibition of gastric acid caused by exogenous GLP-1. These results indicate that GLP-1 and PYY released by intraduodenal fat, in part through CCK-dependent pathways, are major enterogastrones in dogs. This inhibitory action occurs independent of circulating concentrations of somatostatin and gastrin and appears to involve a GLP-1 receptor distinct from that mediating incretin effects.