4-Aminophenyl acetamides and propanamides as potent transient receptor potential vanilloid 1 (TRPV1) ligands
- 주제(키워드) Vanilloid receptor 1 , TRPV1 antagonists , Analgesic
- 주제(기타) Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic
- 설명문(일반) [Kim, Changhoon; Ann, Jihyae; Lee, Sunho; Lee, Jeewoo] Seoul Natl Univ, Coll Pharm, Lab Med Chem, Seoul 08826, South Korea; [Kim, Eunhye; Choi, Sun] Ewha Womans Univ, Coll Pharm, Grad Sch Pharmaceut Sci, Natl Leading Res Lab Mol Modeling & Drug Design, Seoul 03760, South Korea; [Blumberg, Peter M.] NCI, Lab Canc Biol & Genet, Ctr Canc Res, NIH, Bethesda, MD 20892 USA; [Frank-Foltyn, Robert; Bahrenberg, Gregor; Stockhause, Hannelore; Christoph, Thomas] Grunenthal GmbH, Grunenthal Innovat, D-52078 Aachen, Germany
- 등재 SCIE, SCOPUS
- 발행기관 PERGAMON-ELSEVIER SCIENCE LTD
- 발행년도 2018
- URI http://www.dcollection.net/handler/ewha/000000156202
- 본문언어 영어
- Published As http://dx.doi.org/10.1016/j.bmc.2018.07.040
초록/요약
A series of 2-(3,5-substituted 4-aminophenyl)acetamide and propanamide derivatives were investigated as human TRPV1 antagonists. The analysis of the structure-activity relationship indicated that 2-(3,5-dihalo 4-aminophenyl)acetamide analogues displayed excellent antagonism of hTRPV1 activation by capsaicin and showed improved potency compared to the corresponding propanamides. The most potent antagonist (36) exhibited potent and selective antagonism for hTRPV1 not only to capsaicin but also to NADA and elevated temperature; however, it only displayed weak antagonism to low pH. Further studies indicated that oral administration of antagonist 36 blocked the hypothermic effect of capsaicin in vivo but demonstrated hyperthermia at that dose. A docking study of 36 was performed in our established hTRPV1 homology model to understand its binding interactions with the receptor and to compare with that of previous antagonist 1.
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