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

Research output: Contribution to journalArticleResearchpeer-review

19 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

Cite this

Magnani, F., Pappas, C. G., Crook, T., Magafa, V., Cordopatis, P. A., Ishiguro, S., Ohta, N., Selent, J., Bosnyak, S., Jones, E. S., Gerothanassis, I. P., Tamura, M., Widdop, R. E., & Tzakos, A. G. (2014). Electronic sculpting of ligand-GPCR subtype selectivity: the case of angiotensin II. ACS Chemical Biology, 9(7), 1420 - 1425. https://doi.org/10.1021/cb500063y