MDR-652
目录号 : GC39828MDR-652 is a potent and specific agonist of transient receptor potential vanilloid 1 (TRPV1) with Ki of 11.4 nM and 23.8 nM for hTRPV1 and rTRPV1, respectively. MDR-652 has excellent and dose-dependent analgesic activity.
Cas No.:1933528-96-1
Sample solution is provided at 25 µL, 10mM.
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MDR-652 is a potent and specific agonist of transient receptor potential vanilloid 1 (TRPV1) with Ki of 11.4 nM and 23.8 nM for hTRPV1 and rTRPV1, respectively. MDR-652 has excellent and dose-dependent analgesic activity.
[1] Jihyae Ann, et al. J Med Chem. 2020 Jan 9;63(1):418-424.
Cas No. | 1933528-96-1 | SDF | |
Canonical SMILES | O=C(NC1=CC=C(CO)C(F)=C1)NCC2=C(C3=CC=CC(Cl)=C3)N=C(C(C)(C)C)S2 | ||
分子式 | C22H23ClFN3O2S | 分子量 | 447.95 |
溶解度 | DMSO: 250 mg/mL (558.10 mM) | 储存条件 | Store at -20°C |
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1 mg | 5 mg | 10 mg | |
1 mM | 2.2324 mL | 11.162 mL | 22.3239 mL |
5 mM | 0.4465 mL | 2.2324 mL | 4.4648 mL |
10 mM | 0.2232 mL | 1.1162 mL | 2.2324 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 | |||
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% DMSO % % Tween 80 % saline | ||||||||||
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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,
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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 (S)-N-(3-isopropylphenyl)-2-(5-phenylthiazol-2-yl)pyrrolidine-1-carboxamide as potent and brain-penetrant TRPV1 antagonist
Eur J Med Chem 2022 Apr 5;233:114191.PMID:35263708DOI:10.1016/j.ejmech.2022.114191
Transient receptor potential vanilloid 1 (TRPV1) antagonists can inhibit the transmission of nociceptive signals from the peripheral to the central nervous system (CNS), providing a new strategy for pain relief. In this work, in order to develop potent, CNS-penetrant, and orally available TRPV1 antagonists, three series of novel molecules based on the key pharmacophore structures of classic TRPV1 ligands SB-705498 and MDR-652 were designed and synthesized. Through systematic in vitro and in vivo bioassays, (S)-N-(3-isopropylphenyl)-2-(5-phenylthiazol-2-yl)pyrrolidine-1-carboxamide (7q) was finally identified, which had enhanced TRPV1 antagonistic activity (IC50 (capsaicin) = 2.66 nM), excellent CNS penetration (brain/plasma ratio = 1.66), favorable mode-selectivity, good bioavailability, and no side effects of hyperthermia. Molecular docking and dynamics studies indicated that the high binding affinity of compound 7q to TRPV1 was related to multiple interactions, which resulted in significant conformational changes of TRPV1. Overall, our findings have led to a potent, mode-selective, and CNS-penetrant TRPV1 antagonist as a valuable lead for development of novel TRPV1 antagonists.