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Structure activity relationships of benzyl C-region analogs of 2-(3-fluoro-4-methylsulfonamidophenyl)propanamides as potent TRPV1 antagonists
- Structure activity relationships of benzyl C-region analogs of 2-(3-fluoro-4-methylsulfonamidophenyl)propanamides as potent TRPV1 antagonists
- Ann, Jihyae; Jung, Aeran; Kim, Mi-Yeon; Kim, Hyuk-Min; Ryu, HyungChul; Kim, Sunjoo; Kang, Dong Wook; Hong, Sunhye; Cui, Minghua; Choi, Sun; Blumberg, Peter M.; Frank-Foltyn, Robert; Bahrenberg, Gregor; Stockhausen, Hannelore; Christoph, Thomas; Lee, Jeewoo
- Ewha Authors
- SCOPUS Author ID
- Issue Date
- Journal Title
- BIOORGANIC & MEDICINAL CHEMISTRY
- 0968-0896; 1464-3391
- vol. 23, no. 21, pp. 6844 - 6854
- Vanilloid receptor 1; TRPV1 antagonists; Analgesic
- PERGAMON-ELSEVIER SCIENCE LTD
- SCI; SCIE; SCOPUS
- A series of 2-substituted 4-(trifluoromethyl)benzyl C-region analogs of 2-(3-fluoro-4-methylsulfonamidophenyl)propanamides were investigated for hTRPV1 antagonism. The analysis indicated that the phenyl C-region derivatives exhibited better antagonism than those of the corresponding pyridine surrogates for most of the series examined. Among the phenyl C-region derivatives, the two best compounds 43 and 445 antagonized capsaicin selectively relative to their antagonism of other activators and showed excellent potencies with K-i(CAP) = 0.3 nM. These two compounds blocked capsaicin-induced hypothermia, consistent with TRPV1 as their site of action, and they demonstrated promising analgesic activities in a neuropathic pain model without hyperthermia. The docking study of 445 in our hTRPV1 homology model indicated that its binding mode was similar with that of its pyridine surrogate in the A- and B-regions but displayed a flipped configuration in the C-region. (C) 2015 Elsevier Ltd. All rights reserved.
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