Electronic Sculpting of Ligand-GPCR Subtype Selectivity: The Case of Angiotensin II

Abstract

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.

Involvement of angiotensin II type 2 receptor (AT2R) signaling in human pancreatic ductal adenocarcinoma (PDAC): a novel AT2R agonist effectively attenuates growth of PDAC grafts in mice

“…31 This novel AT2R agonist, bearing the peptide sequence DRVYIYPF, significantly stimulates neurite outgrowth in AT2R over-expressing PC12W rat pheochromocytoma cell line, in a dose-dependent manner. 31 In the same study we pinpointed that this compound served as a negative regulator of AT1R signaling since it was able to inhibit MCF-7 breast carcinoma cellular proliferation in the low nanomolar range. 31 These results suggested that this novel AT2R agonist binds selectively to the AT2R and its biological activity is equally strong as an endogenous ligand Ang II.…”

“…31 In the same study we pinpointed that this compound served as a negative regulator of AT1R signaling since it was able to inhibit MCF-7 breast carcinoma cellular proliferation in the low nanomolar range. 31 These results suggested that this novel AT2R agonist binds selectively to the AT2R and its biological activity is equally strong as an endogenous ligand Ang II. Therefore, this novel AT2R agonist can serve as a valuable compound for AT2R-targeted stimulation and may control pathological conditions associated with Ang IIreceptor signaling, such as hypertension, coronary artery disease, kidney disease and various cancers.…”

“…31 Through this strategy an AT2R high affinity (Ki D 3 nM) agonist analog that exerted 18.000-fold higher selectivity for AT2R versus AT1R was obtained. 31 This novel AT2R agonist, bearing the peptide sequence DRVYIYPF, significantly stimulates neurite outgrowth in AT2R over-expressing PC12W rat pheochromocytoma cell line, in a dose-dependent manner.…”

“…31 Through this strategy an AT2R high affinity (Ki D 3 nM) agonist analog that exerted 18.000-fold higher selectivity for AT2R versus AT1R was obtained. 31 This novel AT2R agonist, bearing the peptide sequence DRVYIYPF, significantly stimulates neurite outgrowth in AT2R over-expressing PC12W rat pheochromocytoma cell line, in a dose-dependent manner. 31 In the same study we pinpointed that this compound served as a negative regulator of AT1R signaling since it was able to inhibit MCF-7 breast carcinoma cellular proliferation in the low nanomolar range.…”

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“…Establishing ligands that will present enhanced selectivity for AT 2 R vs. AT 1 R is based on the fact that AT 2 R antagonizes the functions of AT 1 R. Activation of AT 2 R leads to apoptosis, antiproliferation and vasodilation, whereas activation of AT 1 R leads to cellular growth, proliferation and vasoconstriction 40 . Wan et al, synthesized the first selective nonpeptide AT 2 R agonist M024/C21 (Fig.…”