Halogenation of 4-hydroxy-3-methoxybenzyl thiourea TRPV1 agonists showed enhanced antagonism to capsaicin

doi:10.1016/j.bmcl.2006.09.059

Bioorganic & Medicinal Chemistry Letters

Volume 17, Issue 1, 1 January 2007, Pages 214-219

https://doi.org/10.1016/j.bmcl.2006.09.059 Get rights and content

Abstract

Selected potent TRPV1 agonists (1–6) have been modified by 5- or 6-halogenation on the aromatic A-region to analyze their effects on potency and efficacy (agonism versus antagonism). The halogenation caused enhanced functional antagonism at TRPV1 compared to the corresponding prototype agonists. The analysis of SAR indicated that the antagonism was enhanced as the size of the halogen increased (I > Br > Cl) and when the 6-position was halogenated. Compounds 23c and 31b were found to be potent full antagonists with K_i (as functional antagonist) = 23.1 and 30.3 nM in rTRPV1/CHO system, respectively.

Graphical abstract

Selected potent TRPV1 agonists have been modified by 5- or 6-halogenation on the aromatic A-region to analyze their effects on potency and efficacy (agonism versus antagonism).

Section snippets

Acknowledgments

This work was supported by Grant R01-2004-000-10132-0 from the Basic Research Program of the Korea Science and Engineering Foundation and this research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. We thank Matthew A. Morgan, Andrew K. Tao, and Christopher B. Ryder for technical assistance.

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Halogenation of 4-hydroxy/amino-3-methoxyphenyl acetamide TRPV1 agonists showed enhanced antagonism to capsaicin
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Citation Excerpt :
We describe here that halogenation at the 5-position of our TRPV1 ligands possessing an amide B-region was more effective than halogenation at the 6-position to confer antagonism. This contrasts with the SAR we have previously reported for halogenated analogues with a thiourea containing B-region.22 We conclude that halogenated analogues with an amide containing B-region behave more like RTX-related ligands, whereas those with a thiourea containing B-region behave more like capsaicinoid-type ligands.
As an extension of our analysis of the effect of halogenation on thiourea TRPV1 agonists, we have now modified selected 4-hydroxy(or 4-amino)-3-methoxyphenyl acetamide TRPV1 agonists by 5- or 6-halogenation on the aromatic A-region and evaluated them for potency for TRPV1 binding and regulation and for their pattern of agonism/antagonism (efficacy). Halogenation shifted the functional activity at TRPV1 toward antagonism with a greater extent of antagonism as the size of the halogen increased (I > Br > Cl), as previously observed for the thiourea series. The extent of antagonism was greater for halogenation at the 5-position than at the 6-position, in contrast to SAR for the thiourea series. In this series, compounds 55 and 75 showed the most potent antagonism, with K_i (ant) = 2.77 and 2.19 nM, respectively, on rTRPV1 expressed in Chinese hamster ovary cells. The compounds were thus ca. 40–60-fold more potent than 6′-iodononivamide.
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Halogenation of 4-hydroxy-3-methoxybenzyl thiourea TRPV1 agonists showed enhanced antagonism to capsaicin

Abstract

Graphical abstract

Section snippets

Acknowledgments

Trends in Pharmacol. Sci.

Cell

Neuron

Life Sci.

Bioorg. Med. Chem.

Bioorg. Med. Chem.

Bioorg. Med. Chem. Lett.

Bioorg. Med. Chem. Lett.

Pharmacol. Rev.