A series of carbonate analogues of 5′-halogenated RTX have been investigated in order to examine the effect of the carbonate group as a linker and the role of halogens in the reversal of activity from agonism to antagonism for rat and human TRPV1 heterologously expressed in Chinese hamster ovary cells. The carbonate analogues showed similar activities to the corresponding RTX derivatives in rat TRPV1 but lower potency in human TRPV1. 5-Halogenation converted the agonists to partial agonists or full antagonists and the extent of antagonism reflected the order of I > Br > Cl > F, with a somewhat greater extent of antagonism for the derivatives of the 4-amino RTX surrogates compared to the corresponding derivatives of RTX itself. The carbonate analogues of I-RTX (60) and 5-bromo-4-amino-RTX (66) were potent and full antagonists with Ki(ant) = 2.23 and 2.46 nM, respectively, for rat TRPV1, which were ca. 5-fold more potent than I-RTX (2) under our conditions. The conformational analysis of the I-RTX-carbonate (60) indicated that its bent conformation was similar to that of I-RTX, consistent with compound 60 and I-RTX showing comparable potent antagonism.
Bibliographical noteFunding Information:
This research was supported by Grant R11-2007-107-02001-0 from the National Research Foundation of Korea (NRF) , by Grants from the National Leading Research Lab (NLRL) program ( 2011-0028885 ) funded by the Ministry of Education, Science and Technology (MEST) and the National Research Foundation of Korea (NRF) , and by the Intramural Research Program of the National Institutes of Health, Center for Cancer Research, National Cancer Institute ( Z1A BC 005270 ).
- Molecular modelling
- Partial agonist
- TRPV1 agonist
- TRPV1 antagonist