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ACS Chem Biol. 2014 Jul 18;9(7):1420-5. doi: 10.1021/cb500063y. Epub 2014 May 14.

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

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Laboratory of Molecular Biology, Medical Research Council , Cambridge CB2 0QH, United Kingdom.


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.

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