Halogenation of 4-hydroxy/amino-3-methoxyphenyl acetamide TRPV1 agonists showed enhanced antagonism to capsaicin.
Bioorg Med Chem
; 18(22): 8092-105, 2010 Nov 15.
Article
em En
| MEDLINE
| ID: mdl-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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Benzamidas
/
Capsaicina
/
Canais de Cátion TRPV
/
Acetamidas
Idioma:
En
Ano de publicação:
2010
Tipo de documento:
Article