Ogerin
(Synonyms: ZINC67740571) 目录号 : GC34697
A positive allosteric modulator of GPR68
Cas No.:1309198-71-7
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
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- Purity: >98.50%
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- Datasheet
Ogerin is a positive allosteric modulator of G protein-coupled receptor 68 (GPR68).1 It increases proton-induced cAMP production in HEK293T cells expressing the human receptor in a reporter assay. Ogerin inhibits proton-mediated calcium release in the same cells when used at a concentration of 10 ?M. It impairs contextual, but not cued, fear conditioning in wild-type, but not Gpr68 knockout, mice when administered at a dose of 10 mg/kg.
1.Huang, X.-P., Karpiak, J., Kroeze, W.K., et al.Allosteric ligands for the pharmacologically dark receptors GPR68 and GPR65Nature527(7579)477-483(2015)
| Cas No. | 1309198-71-7 | SDF | |
| 别名 | ZINC67740571 | ||
| Canonical SMILES | OCC1=C(C2=NC(N)=NC(NCC3=CC=CC=C3)=N2)C=CC=C1 | ||
| 分子式 | C17H17N5O | 分子量 | 307.35 |
| 溶解度 | DMSO : 250 mg/mL (813.40 mM) | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 3.2536 mL | 16.2681 mL | 32.5362 mL |
| 5 mM | 0.6507 mL | 3.2536 mL | 6.5072 mL |
| 10 mM | 0.3254 mL | 1.6268 mL | 3.2536 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Ogerin mediated inhibition of TGF-β(1) induced myofibroblast differentiation is potentiated by acidic pH
PLoS One 2022 Jul 28;17(7):e0271608.PMID:35901086DOI:10.1371/journal.pone.0271608.
Transforming growth factor beta (TGF-β) induced myofibroblast differentiation is central to the pathological scarring observed in Idiopathic Pulmonary Fibrosis (IPF) and other fibrotic diseases. Our lab has recently identified expression of GPR68 (Ovarian Cancer Gene Receptor 1, OGR1), a pH sensing G-protein coupled receptor, as a negative regulator of TGF-β induced profibrotic effects in primary human lung fibroblasts (PHLFs). We therefore hypothesized that small molecule activators of GPR68 would inhibit myofibroblast differentiation. Ogerin is a positive allosteric modulator (PAM) of GPR68, inducing a leftward shift of the dose response curve to proton induced signaling. Using PHLFs derived from patients with both non-fibrotic and IPF diagnoses, we show that Ogerin inhibits, and partially reverses TGF-β induced myofibroblast differentiation in a dose dependent manner. This occurs at the transcriptional level without inhibition of canonical TGF-β induced SMAD signaling. Ogerin induces PKA dependent CREB phosphorylation, a marker of Gαs pathway activation. The ability of Ogerin to inhibit both basal and TGF-β induced collagen gene transcription, and induction of Gαs signaling is enhanced at an acidic pH (pH 6.8). Similar findings were also found using fibroblasts derived from dermal, intestinal, and orbital tissue. The biological role of GPR68 in different tissues, cell types, and disease states is an evolving and emerging field. This work adds to the understanding of Gαs coupled GPCRs in fibrotic lung disease, the ability to harness the pH sensing properties of GPR68, and conserved mechanisms of fibrosis across different organ systems.
Allosteric ligands for the pharmacologically dark receptors GPR68 and GPR65
Nature 2015 Nov 26;527(7579):477-83.PMID:26550826DOI:10.1038/nature15699.
At least 120 non-olfactory G-protein-coupled receptors in the human genome are 'orphans' for which endogenous ligands are unknown, and many have no selective ligands, hindering the determination of their biological functions and clinical relevance. Among these is GPR68, a proton receptor that lacks small molecule modulators for probing its biology. Using yeast-based screens against GPR68, here we identify the benzodiazepine drug lorazepam as a non-selective GPR68 positive allosteric modulator. More than 3,000 GPR68 homology models were refined to recognize lorazepam in a putative allosteric site. Docking 3.1 million molecules predicted new GPR68 modulators, many of which were confirmed in functional assays. One potent GPR68 modulator, Ogerin, suppressed recall in fear conditioning in wild-type but not in GPR68-knockout mice. The same approach led to the discovery of allosteric agonists and negative allosteric modulators for GPR65. Combining physical and structure-based screening may be broadly useful for ligand discovery for understudied and orphan GPCRs.
Species-Dependent Enhancement of Ovarian Cancer G Protein-Coupled Receptor 1 Activation by Ogerin
Zoolog Sci 2020 Apr;37(2):103-108.PMID:32282140DOI:10.2108/zs190106.
Ogerin is a positive allosteric modulator of human and mouse ovarian cancer G protein-coupled receptors (OGR1s). In the present study, we found that Ogerin differentially enhances the activation of OGR1 in various animal species. Amino acid residues of OGR1 that are associated with Ogerin are conserved among the species. This suggests that other amino acid residues may be involved in the action of Ogerin. Chimeric receptors between human and zebrafish OGR1s showed that the amino acid residues that determine the species specificity of ogerin-induced enhancement reside in the transmembrane and/or intracellular regions of OGR1. This result highlights the importance of first verifying the effectiveness of Ogerin to the OGR1 of the species of interest at the cellular level prior to analyzing the physiological and pathophysiological roles of OGR1 in the species.
Design, Synthesis, and Characterization of Ogerin-Based Positive Allosteric Modulators for G Protein-Coupled Receptor 68 (GPR68)
J Med Chem 2019 Aug 22;62(16):7557-7574.PMID:31298539DOI:10.1021/acs.jmedchem.9b00869.
G protein-coupled receptor 68 (GPR68) is an understudied orphan G protein-coupled receptor (GPCR). It is expressed most abundantly in the brain, potentially playing important roles in learning and memory. Pharmacological studies with GPR68 have been hindered by lack of chemical tools that can selectively modulate its activity. We previously reported the first small-molecule positive allosteric modulator (PAM), Ogerin (1), and showed that 1 can potentiate proton activity at the GPR68-Gs pathway. Here, we report the first comprehensive structure-activity relationship (SAR) study on the scaffold of 1. Our lead compound resulted from this study, MS48107 (71), displayed 33-fold increased allosteric activity compared to 1. Compound 71 demonstrated high selectivity over closely related proton GPCRs and 48 common drug targets, and was bioavailable and brain-penetrant in mice. Thus, our SAR study has resulted in an improved GPR68 PAM for investigating the physiological and pathophysiological roles of GPR68 in vitro and in vivo.
Mechanical and chemical activation of GPR68 probed with a genetically encoded fluorescent reporter
J Cell Sci 2021 Aug 15;134(16):jcs255455.PMID:34322699DOI:10.1242/jcs.255455.
G-protein-coupled receptor (GPCR) 68 (GPR68, or OGR1) couples extracellular acidifications and mechanical stimuli to G-protein signaling and plays important roles in vascular physiology, neuroplasticity and cancer progression. Inspired by previous GPCR-based reporters, here, we inserted a cyclic permuted fluorescent protein into the third intracellular loop of GPR68 to create a genetically encoded fluorescent reporter of GPR68 activation we call 'iGlow'. iGlow responds to known physiological GPR68 activators such as fluid shear stress and extracellular acidifications. In addition, iGlow responds to Ogerin, a synthetic GPR68-selective agonist, but not to a non-active Ogerin analog, showing the specificity of iGlow-mediated fluorescence signals. Flow-induced iGlow activation is not eliminated by pharmacological modulation of downstream G-protein signaling, disruption of actin filaments or application of GsMTx4, an inhibitor of certain mechanosensitive ion channels activated by membrane stretch. Deletion of the conserved helix 8, proposed to mediate mechanosensitivity in certain GPCRs, does not eliminate flow-induced iGlow activation. iGlow could be useful to investigate the contribution of GPR68-dependent signaling in health and disease.