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

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

    Research output: Contribution to journalArticlepeer-review

    28 Citations (Scopus)
    164 Downloads (Pure)


    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 - 18 Jul 2014


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