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

Kwang Su Lim, Dong Wook Kang, Yong Soo Kim, Myeong Seop Kim, Seul Gi Park, Sun Choi, Larry V. Pearce, Peter M. Blumberg, Jeewoo Lee

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5 Scopus citations


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.

Original languageEnglish
Pages (from-to)299-302
Number of pages4
JournalBioorganic and Medicinal Chemistry Letters
Issue number1
StatePublished - 1 Jan 2011


  • Halogenation
  • Molecular modeling
  • Partial agonist
  • Resiniferatoxin
  • TRPV1 agonist
  • TRPV1 antagonist


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