Structure-activity relationships of the ultrapotent vanilloid resiniferatoxin (RTX): The side chain benzylic methylene

被引：8
作者：
Appendino, Giovanni [1 ]
Ech-Chahad, Abdellah [1 ]
Minassi, Alberto [1 ]
De Petrocellis, Luciano [2 ]
Di Marzo, Vincenzo [3 ]
机构：
[1] Univ Piemonte Orientale, Dipartimento Sci Chim Alimentari Farmaceut & Farm, I-28100 Novara, Italy
[2] CNR, Endocannabinoid Res Grp, Inst Cibernet Eduardo Caianiello, Pozzuoli, NA, Italy
[3] CNR, Endocannabinoid Res Grp, Inst Biomol Chem, I-80078 Pozzuoli, NA, Italy
来源：
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2010年 / 20卷 / 01期
关键词：
Resiniferatoxin (RTX); TRPV1; Structure-activity relationships; Capsaicin; Vanilloids; CAPSAICIN RECEPTOR; DOUBLE-BLIND; BINDING; CANCER;
D O I：
10.1016/j.bmcl.2009.11.035
中图分类号：
R914 [药物化学];
学科分类号：
100701 ;
摘要：
The side chain benzylic methylene is a critical element for the vanilloid activity of resiniferatoxin (2a, RTX), and introduction of branching, oxygen functions, or isosteric substitution at this center proved detrimental, with a decrease of potency of 2-3 orders of magnitude compared to the natural product. Conversely, only a modest erosion of activity was observed upon a-methylation and alpha-methylenation of the side chain. Surprisingly, introduction of an iodine atom in the guaiacyl moiety of the oxygen isoster 2h led to an unexpected and remarkable (> 1000-fold) increase of potency, affording 2i, a compound that outperforms RTX in terms of vanilloid agonism and represents the first one-digit picomolar ligand of a TRP channel discovered to date. (C) 2009 Elsevier Ltd. All rights reserved.
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收藏
页码：97 / 99
页数：3
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