Structure-activity relationships and molecular modeling of the N-(3-pivaloyloxy-2-benzylpropyl)-N′-[4-(methylsulfonylamino)benzyl] thiourea template for TRPV1 antagonism

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:22

Article

Bhondwe, Rahul S.¹  Kang, Dong Wook²  Kim, Myeong Seop¹  Kim, Ho Shin¹  Park, Seul-gi^3,4  Son, Karam^3,4  Choi, Sun^3,4  Kuhs, Krystle A. Lang⁵  Pavlyukovets, Vladimir A.⁵  Pearce, Larry V.⁵  Blumberg, Peter M.⁵  Lee, Jeewoo¹ 

[1] Seoul Natl Univ, Res Inst Pharmaceut Sci, Coll Pharm, Seoul 151742, South Korea

[2] Catholic Univ Deagu, Dept Pharmaceut Sci & Technol, Coll Hlth & Med Sci, Gyongsan 712702, Gyeongsangbuk D, South Korea

[3] Ewha Womans Univ, Natl Leading Res Lab NLRL Mol Modeling & Drug Des, Coll Pharm, Div Life & Pharmaceut Sci, Seoul 120750, South Korea

[4] Ewha Womans Univ, Natl Core Res Ctr Cell Signaling & Drug Discovery, Seoul 120750, South Korea

[5] NCI, Lab Canc Biol & Genet, Ctr Canc Res, NIH, Bethesda, MD 20892 USA

关键词: Vanilloid receptor 1;    TRPV1 antagonist;    Capsaicin;    Resiniferatoxin;    Molecular modeling;   

DOI  :  10.1016/j.bmcl.2012.04.034

来源: Elsevier

【 摘 要 】

The structure-activity relationships of N-(3-acyloxy-2-benzylpropyl)-N'-4-[(methylsulfonylamino) benzyl] thioureas, which represent simplified RTX-based vanilloids, were investigated by varying the distances between the four principal pharmacophores and assessing binding and antagonistic activity on rTRPV1. The analysis indicated that a 3-pivaloyloxy-2-benzylpropyl C-region conferred the best potency in binding affinity and antagonism. The molecular modeling of this best template with the tetrameric homology model of rTRPV1 was performed to identify its binding interactions with the receptor. (C) 2012 Elsevier Ltd. All rights reserved.

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