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.
Bibliographical noteFunding Information:
This research was supported by Grant R11-2007-107-02001-0 from the National Research Foundation of Korea (NRF) , the National Core Research Center (NCRC) program ( R15-2006-020 ) of MEST and NRF through the Center for Cell Signaling & Drug Discovery Research at Ewha Womans University (to S. Choi), and by the Intramural Research Program of the National Institutes of Health, Center for Cancer Research, National Cancer Institute. We thank numerous research fellows for some of the biological analyses.
- Molecular modeling
- Partial agonist
- TRPV1 agonist
- TRPV1 antagonist