Electronic sculpting of ligand-GPCR subtype selectivity: the case of angiotensin II.
ACS Chem Biol
; 9(7): 1420-5, 2014 Jul 18.
Article
in En
| MEDLINE
| ID: mdl-24787922
ABSTRACT
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Angiotensin II
/
Receptor, Angiotensin, Type 2
/
Antineoplastic Agents
Limits:
Female
/
Humans
Language:
En
Journal:
ACS Chem Biol
Year:
2014
Document type:
Article
Affiliation country: