Electronic sculpting of ligand-GPCR subtype selectivity: the case of angiotensin II.
ACS Chem Biol
; 9(7): 1420-5, 2014 Jul 18.
Article
en En
| MEDLINE
| ID: mdl-24787922
GPCR subtypes possess distinct functional and pharmacological profiles, and thus development of subtype-selective ligands has immense therapeutic potential. This is especially the case for the angiotensin receptor subtypes AT1R and AT2R, where a functional negative control has been described and AT2R activation highlighted as an important cancer drug target. We describe a strategy to fine-tune ligand selectivity for the AT2R/AT1R subtypes through electronic control of ligand aromatic-prolyl interactions. Through this strategy an AT2R high affinity (Ki = 3 nM) agonist analogue that exerted 18,000-fold higher selectivity for AT2R versus AT1R was obtained. We show that this compound is a negative regulator of AT1R signaling since it is able to inhibit MCF-7 breast carcinoma cellular proliferation in the low nanomolar range.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Angiotensina II
/
Receptor de Angiotensina Tipo 2
/
Antineoplásicos
Límite:
Female
/
Humans
Idioma:
En
Revista:
ACS Chem Biol
Año:
2014
Tipo del documento:
Article
País de afiliación:
Reino Unido
Pais de publicación:
Estados Unidos