Receptor activity and conformational analysis of 5′-halogenated resiniferatoxin analogs as TRPV1 ligands

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:21

Article

Lim, Kwang Su¹  Kang, Dong Wook¹  Kim, Yong Soo¹  Kim, Myeong Seop¹  Park, Seul-Gi^3,4  Choi, Sun^3,4  Pearce, Larry V.²  Blumberg, Peter M.²  Lee, Jeewoo¹ 

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

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

[3] Ewha Womans Univ, 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

关键词: TRPV1 agonist;    TRPV1 antagonist;    Partial agonist;    Halogenation;    Resiniferatoxin;    Molecular modeling;   

DOI  :  10.1016/j.bmcl.2010.11.012

来源: Elsevier

【 摘 要 】

A series of 5'-halogenated resiniferatoxin analogs have been investigated in order to examine the effect of halogenation in the A-region on their binding and the functional pattern of agonism/antagonism for rat TRPV1 heterologously expressed in Chinese hamster ovary cells. Halogenation at the 5-position in the A-region of RTX and of 4-amino RTX shifted the agonism of parent compounds toward antagonism. The extent of antagonism was greater as the size of the halogen increased (I > Br > Cl > F) while the binding affinities were similar, as previously observed for our potent agonists. In this series, 5-bromo-4-amino RTX (39) showed very potent antagonism with K-i (ant) = 2.81 nM, which was thus 4.5-fold more potent than 5'-iodo RTX, previously reported as a potent TRPV1 antagonist. Molecular modeling analyses with selected agonists and the corresponding halogenated antagonists revealed a striking conformational difference. The 3-methoxy of the A-region in the agonists remained free to interact with the receptor whereas in the case of the antagonists, the compounds assumed a bent conformation, permitting the 3-methoxy to instead form an internal hydrogen bond with the C4-hydroxyl of the diterpene. (C) 2010 Elsevier Ltd. All rights reserved.

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