Asymmetric synthesis and receptor activity of chiral simplified resiniferatoxin (sRTX) analogues as transient receptor potential vanilloid 1 (TRPV1) ligands

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:24

Article

Kim, Myeong Seop¹  Ki, Yooran¹  Ahn, Song Yeon¹  Yoon, Suyoung¹  Kim, Sung-Eun¹  Park, Hyeung-Geun¹  Sun, Wei²  Son, Karam^3,4  Cui, Minghua^3,4  Choi, Sun^3,4  Pearce, Larry V.⁵  Esch, Timothy E.⁵  DeAndrea-Lazarus, Ian A.⁵  Blumberg, Peter M.⁵  Lee, Jeewoo¹ 

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

[2] Shenyang Pharmaceut Univ, Shenyang 110016, Liaoning, Peoples R China

[3] Ewha Womans Univ, Grad Sch Pharmaceut Sci, Coll Pharm, Natl Leading Res Lab Mol Modeling & Drug Design, Seoul 120750, South Korea

[4] Ewha Womans Univ, Global Top Res Program 5, 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.2013.10.064

来源: Elsevier

【 摘 要 】

The chiral isomers of the two potent simplified RTX-based vanilloids, compounds 2 and 3, were synthesized employing highly enantioselective PTC alkylation and evaluated as hTRPV1 ligands. The analysis indicated that the R-isomer was the eutomer in binding affinity and functional activity. The agonism of compound 2R was comparable to that of RTX. Docking analysis of the chiral isomers of 3 suggested the basis for its stereospecific activity and the binding mode of 3R. (C) 2013 Elsevier Ltd. All rights reserved.

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