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

Title
Receptor activity and conformational analysis of 5′-halogenated resiniferatoxin analogs as TRPV1 ligands
Authors
Lim K.S.Kang D.W.Kim Y.S.Kim M.S.Park S.-G.Choi S.Pearce L.V.Blumberg P.M.Lee J.
Ewha Authors
최선
SCOPUS Author ID
최선scopus
Issue Date
2011
Journal Title
Bioorganic and Medicinal Chemistry Letters
ISSN
0960-894XJCR Link
Citation
vol. 21, no. 1, pp. 299 - 302
Indexed
SCI; SCIE; SCOPUS WOS scopus
Abstract
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. © 2010 Elsevier Ltd. All rights reserved.
DOI
10.1016/j.bmcl.2010.11.012
Appears in Collections:
약학대학 > 약학과 > Journal papers
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