Electronic sculpting of ligand-GPCR subtype selectivity: the case of angiotensin II

Francesca Magnani, Charalampos G Pappas, Tim Crook, Vassiliki Magafa, Paul A Cordopatis, Susumu Ishiguro, Naomi Ohta, Jana Selent, Sanja Bosnyak, Emma S Jones, Ioannis P Gerothanassis, Masaaki Tamura, Robert E Widdop, Andreas G Tzakos

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28 Citations (Scopus)


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.
Original languageEnglish
Pages (from-to)1420 - 1425
Number of pages6
JournalACS Chemical Biology
Issue number7
Publication statusPublished - 2014

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