MCHr1 antagonist 2
目录号 : GC31505
MCHr1antagonist2是一种黑色素聚集激素受体1(melaninconcentratinghormonereceptor1)拮抗剂，IC50值为65nM；MCHr1antagonist2同时抑制hERG，在IMR-32细胞中，IC50值为4.0nM。
Cas No.:863115-70-2
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Kinase experiment: | In 96-well plates, IMR-32 cells (I3.4.2) membranes (6 μg/well) are incubated in the presence of test compound (MCHr1 antagonist 2) in binding buffer (25 mM HEPES pH 7.4, 1 mM CaCl2, 5 mM MgCl2 and 0.5% BSA) and with 0.05 nM [125I]MCH (2200 Ci/mmol) per well for 60 min at room temperature. Nonspecific binding controls consist of I3.4.2 membranes, 0.05 nM [125I]MCH, and 300 nM human MCH. Total binding controls of I3.4.2 membranes and 0.05 nM [125I]MCH are also included on each plate. The plates are centrifuged for 5 min at 1380 g in a GS-6R desktop centrifuge. The reaction buffer is carefully aspirated from each well without disturbing the pellet. Wash buffer (25 mM HEPES, pH 7.4, 1 mM CaCl2, 5 mM MgCl2, and 0.5 M NaCl) is added to each well and then transferred to a 0.5% polyethylenimine-treated GF/B filtration plate using a plate Filtermate Harvester. The filter plate is washed three times with wash buffer, MicroScint 20 is added to each well, and the plate is read using a Topcount microplate scintillation counter[1]. |
References: [1]. Lynch JK, et al. Optimization of chromone-2-carboxamide melanin concentrating hormone receptor 1 antagonists: assessment of potency, efficacy, and cardiovascular safety. J Med Chem. 2006 Nov 2;49(22):6569-84. | |
MCHr1 antagonist 2 is an antagonist of melanin concentrating hormone receptor 1, with an IC50 of 65 nM; MCHr1 antagonist 2 also inhibits hERG, with an IC50 of 4.0 nM in IMR-32 cells.
MCHr1 antagonist 2 (Compound 30) is an antagonist of melanin concentrating hormone receptor 1, with an IC50 of 65 nM. MCHr1 antagonist 2 has inhibitory effects on Ca2+ flux, and hERG, with IC50s of 196 ± 30 nM and 4.0 ± 0.8 nM, respectively, in IMR-32 cells[1].
[1]. Lynch JK, et al. Optimization of chromone-2-carboxamide melanin concentrating hormone receptor 1 antagonists: assessment of potency, efficacy, and cardiovascular safety. J Med Chem. 2006 Nov 2;49(22):6569-84.
| Cas No. | 863115-70-2 | SDF | |
| Canonical SMILES | O=C(C1=CC(C2=CC(F)=CC=C2O1)=O)NC3CCN(CC4=CC=C(OCO5)C5=C4)CC3 | ||
| 分子式 | C23H21FN2O5 | 分子量 | 424.42 |
| 溶解度 | Soluble in DMSO | 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 | 2.3562 mL | 11.7808 mL | 23.5616 mL |
| 5 mM | 0.4712 mL | 2.3562 mL | 4.7123 mL |
| 10 mM | 0.2356 mL | 1.1781 mL | 2.3562 mL |
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| 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 |
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| % 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。
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Discovery of (3-(4-(2-Oxa-6-azaspiro[3.3]heptan-6-ylmethyl)phenoxy)azetidin-1-yl)(5-(4-methoxyphenyl)-1,3,4-oxadiazol-2-yl)methanone (AZD1979), a Melanin Concentrating Hormone Receptor 1 (MCHr1) Antagonist with Favorable Physicochemical Properties
A novel series of melanin concentrating hormone receptor 1 (MCHr1) antagonists were the starting point for a drug discovery program that culminated in the discovery of 103 (AZD1979). The lead optimization program was conducted with a focus on reducing lipophilicity and understanding the physicochemical properties governing CNS exposure and undesired off-target pharmacology such as hERG interactions. An integrated approach was taken where the key assay was ex vivo receptor occupancy in mice. The candidate compound 103 displayed appropriate lipophilicity for a CNS indication and showed excellent permeability with no efflux. Preclinical GLP toxicology and safety pharmacology studies were without major findings and 103 was taken into clinical trials.
Novel MCH1 receptor antagonists: a patent review
Introduction: The cyclic neuropeptide melanin-concentrating hormone (MCH) shows appetite-stimulating effects indicating an involvement in obesity. Large efforts have been invested in discovery programs to identify novel MCH1 receptor (MCHR1) antagonists. Other indications where MCHR1 antagonists may have a potential use include: anxiety/depression and, more recently, inflammatory responses in the gastrointestinal tract.
Areas covered: The current review covers the patent literature on MCHR1 antagonists published from November 2010 to March 2014. The applications have been grouped by filing company, and weight has been put on commenting compounds with disclosed in vivo biological data.
Expert opinion: Achieving sufficient separation of the human EtheR-a-Go-go channel has prevented many programs from reaching the clinic. For clinical programs, CNS exposure seems to have been a major challenge. Although clinical studies of MCHR1 antagonists have not been able to conclusively evaluate the concept, the body of evidence suggesting a role for MCHR1 antagonists in weight management is strong and novel chemical series still appear in the patent literature. An MCHR1 antagonist with the appropriate physical chemical properties is needed to convincingly evaluate the MCHR1 concept for obesity treatment and, as knowledge from previous programs are shared, the discovery of such a compound should be achievable.
Efficacy of the MCHR1 antagonist N-[3-(1-{[4-(3,4-difluorophenoxy)phenyl]methyl}(4-piperidyl))-4-methylphenyl]-2-methylpropanamide (SNAP 94847) in mouse models of anxiety and depression following acute and chronic administration is independent of hippocampal neurogenesis
Melanin-concentrating hormone (MCH) is a hypothalamic neuropeptide that plays a role in the modulation of food intake and mood. In rodents, the actions of MCH are mediated via the MCHR1 receptor. The goal of this study was to investigate the effects of acute (1 h) and chronic (28 days) p.o. dosing of a novel MCHR1 antagonist, N-[3-(1-{[4-(3,4-difluorophenoxy)-phenyl]methyl}(4-piperidyl))-4-methylphenyl]-2-methylpropanamide (SNAP 94847), in three mouse models predictive of antidepressant/anxiolytic-like activity: novelty suppressed feeding (NSF) in 129S6/SvEvTac mice and light/dark paradigm (L/D) and forced swim test (FST) in BALB/cJ mice. A significant increase in the time spent in the light compartment of the L/D box was observed in response to acute and chronic treatment with SNAP 94847. An anxiolytic/antidepressant-like effect was found in the NSF test after acute and chronic treatment, whereas no effect was observed in the FST. Because neurogenesis in the dentate gyrus has been shown to be a requirement for the effects of antidepressants in the NSF test, we investigated whether neurogenesis was required for the effect of SNAP 94847. We showed that chronic treatment with SNAP 94847 stimulated proliferation of progenitors in the dentate gyrus. The efficacy of SNAP 94847 in the NSF test, however, was unaltered in mice in which neurogenesis was suppressed by X-irradiation. These results indicate that SNAP 94847 has a unique anxiolytic-like profile after both acute and chronic administration and that its mechanism of action is distinct from that of selective serotonin reuptake inhibitors and tricyclic antidepressants.
hERG Optimization of Benzofuro-Pyridine and Pyrazino-Indole Derivatives as MCHR1 Antagonists
Obesity is a global epidemic associated with multiple severe diseases. Several pharmacotherapies have been investigated including the antagonists of melanin concentrating hormone receptor 1 (MCHR1). The design, synthesis, and biological studies of novel MCHR1 antagonists based on benzofuro-pyridine and pyrazino-indole scaffold was performed. We confirmed that fine-tuning lipophilicity and basic pKa by modifying the benzyl group and introducing different substituents on the aliphatic nitrogen sidechain decreases both hERG inhibition and metabolic clearance. We have succeeded to develop excellent in vitro parameters in the case of compounds 17 (4-[(5-chloropyridin-2-yl)methoxy]-1-[4-(2-hydroxyethyl)-8-oxa-4-azatricyclo[7.4.0.02 ,7 ]trideca-1(13),2(7),9,11-tetraen-11-yl]-1,2-dihydropyridin-2-one monohydrochloride) and 23 g (4-[(5-chloropyridin-2-yl)methoxy]-1-(1,2,3,4-tetrahydropyrazino[1,2-a]indol-8-yl)pyridin-2(1H)-one monohydrochloride), which can be considered as valuable tools for further pharmacological investigation.
Synthesis and evaluation of 2-amino-8-alkoxy quinolines as MCHr1 antagonists. Part 2
The continued SAR investigation of 2-amino-8-alkoxy quinolines as melanin concentrating hormone receptor-1 (MCHr1) antagonists is reported. Prior hit-to-lead efforts resulted in the identification of 1 as a robust MCHr1 antagonist. Further delineation of the structural parameters essential for MCHr1-binding affinity of this class of nontraditional GPCR ligands resulted in the identification of compounds such as 33, 34 and 37, which demonstrate single digit nanomolar antagonism of MCHr1-mediated Ca(2+) release. The synthesis and biological evaluation of these compounds are reported.