Halogenation of 4-hydroxy/amino-3-methoxyphenyl acetamide TRPV1 agonists showed enhanced antagonism to capsaicin.

Kang DW, Kim YS, Lim KS, Kim MS, Pearce LV, Pavlyukovets VA, Tao AK, Lang-Kuhs KA, Blumberg PM, Lee J
Bioorg Med Chem. 2010 18 (22): 8092-105

PMID: 20937561 · PMCID: PMC3420354 · DOI:10.1016/j.bmc.2010.09.001

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 2.19nM, respectively, on rTRPV1 expressed in Chinese hamster ovary cells. The compounds were thus ca. 40-60-fold more potent than 6'-iodononivamide.

Copyright © 2010 Elsevier Ltd. All rights reserved.

MeSH Terms (12)

Acetamides Animals Benzamides Capsaicin CHO Cells Cricetinae Cricetulus Halogenation Rats Structure-Activity Relationship Thiourea TRPV Cation Channels

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