Referenced in: none

Automatically associated channels: TRP , TRPV , TRPV1

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

Authors: Dong Wook Kang, Yong Soo Kim, Kwang Su Lim, Myeong Seop Kim, Larry V Pearce, Vladimir A Pavlyukovets, Andy K Tao, Krystle A Lang-Kuhs, Peter M Blumberg, Jeewoo Lee

Journal, date & volume: Bioorg. Med. Chem., 2010 Nov 15 , 18, 8092-105

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/20937561

Abstract
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.