Receptor activity and conformational analysis of 5'-halogenated resiniferatoxin analogs as TRPV1 ligands.
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.
Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea.
Kwang Su
KS
Lim
Dong Wook
DW
Kang
Yong Soo
YS
Kim
Myeong Seop
MS
Kim
Seul-Gi
SG
Park
Sun
S
Choi
Larry V
LV
Pearce
Peter M
PM
Blumberg
Jeewoo
J
Lee
D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004224:Diterpenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D054879:Halogenation; D008024:Ligands; D008958:Models, Molecular; D051381:Rats; D050916:TRPV Cation Channels / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000378:metabolism
D004224:Diterpenes; D008024:Ligands; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat; C024353:resiniferatoxin