4-Aminophenyl acetamides and propanamides as potent transient receptor potential vanilloid 1 (TRPV1) ligands. Issue 15 (15th August 2018)

• Record Type: Journal Article
• Authors: Kim, Changhoon; Ann, Jihyae; Lee, Sunho; Kim, Eunhye; Choi, Sun; Blumberg, Peter M.; Frank-Foltyn, Robert; Bahrenberg, Gregor; Stockhausen, Hannelore; Christoph, Thomas; Lee, Jeewoo
• Is Part Of: Bioorganic & medicinal chemistry. Volume 26:Issue 15(2018)
• Page Start: 4509
• Page End: 4517
• Publication Date: 2018-08-15
• Subjects: Vanilloid receptor 1 -- TRPV1 antagonists -- Analgesic; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2018.07.040
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: 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 h TRPV1 activation by capsaicin and showed improved potency compared to the corresponding propanamides. The most potent antagonist (36 ) exhibited potent and selective antagonism for h TRPV1 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 antagonist36 blocked the hypothermic effect of capsaicin in vivo but demonstrated hyperthermia at that dose. A docking study of36 was performed in our established h TRPV1 homology model to understand its binding interactions with the receptor and to compare with that of previous antagonist1 .