Magnani, FrancescaPappas, Charalampos G.Crook, TimMagafa, VassilikiCordopatis, PaulIshiguro, SusumuOhta, NaomiSelent, JanaBosnyak, SanjaJones, Emma S.Gerothanassis, Ioannis P.Tamura, MasaakiWiddop, Robert E.Tzakos, Andreas G.2024-01-162024-01-162014Magnani F, Pappas CG, Crook T, Magafa V, Cordopatis P, Ishiguro S, et al. Electronic sculpting of ligand-GPCR subtype selectivity: the case of angiotensin II. ACS Chem Biol. 2014 Apr 30;9(7):1420-5. DOI: 10.1021/cb500063y1554-8929http://hdl.handle.net/10230/58699GPCR 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.application/pdfengThis is an open access article published under a Creative Commons Attribution (CC-BY) License, which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited.Angiotensina IIMedicamentsCàncerinfo:eu-repo/semantics/articlehttp://dx.doi.org/10.1021/cb500063yinfo:eu-repo/semantics/openAccess