New benzodiazepine-based gamma-turn mimetics with one or two amino acid side chains were synthesized. The gamma-turn mimetics were incorporated into angiotensin II (Ang II) replacing the Val(3)-Tyr(4)-Ile(5) or Tyr(4)-Ile(5) peptide segments. All of the resulting pseudopeptides displayed high AT(2)/AT(1) receptor selectivity and exhibited AT(2) receptor affinity in the low nanomolar range. Molecular modeling was used to investigate whether the compounds binding to the AT(2) receptor could position important structural elements in common areas. A previously described benzodiazepine-based gamma-turn mimetic with high affinity for the AT(2) receptor was also included in the modeling. It was found that the molecules, although being structurally quite different, could adopt the same binding mode/interaction pattern in agreement with the model hypothesis. The pseudopeptides selected for agonist studies were shown to act as AT(2) receptor agonists being able to induce outgrowth of neurite cells, stimulate p42/p44(mapk), and suppress proliferation of PC12 cells.
"Furthermore, due to its peptidic nature, CGP42112A could not be used readily in in vivo studies. Anders Hallberg and colleagues, as recently summarized by Steckelings et al. (2010a,b) and Unger and Dahlof (2010), have characterized the properties of several non-peptidic compounds derived from the prototype non-selective AT1/AT2 receptor agonist L-162,313 (Wan et al., 2004; Georgsson et al., 2005, 2006; Rosenstrom et al., 2005; Wu et al., 2006; Murugaiah et al., 2007). One of these ligands, the M24 compound (originally called C21; Wan et al., 2004; Georgsson et al., 2007), exhibits high affinity for the AT2R (0.4 nM), but very low affinity for the AT1R (>10,000 nM) and acts as an AT2R agonist (Wan et al., 2004). "
[Show abstract][Hide abstract] ABSTRACT: Amyloid-β peptide deposition, abnormal hyperphosphorylation of tau, as well as inflammation and vascular damage, are associated with the development of Alzheimer's disease (AD). Angiotensin II (Ang II) is a peripheral hormone, as well as a neuropeptide, which binds two major receptors, namely the Ang II type 1 receptor (AT1R) and the type 2 receptor (AT2R). Activation of the AT2R counteracts most of the AT1R-mediated actions, promoting vasodilation, decreasing the expression of pro-inflammatory cytokines, both in the brain and in the cardiovascular system. There is evidence that treatment with AT1R blockers (ARBs) attenuates learning and memory deficits. Studies suggest that the therapeutic effects of ARBs may reflect this unopposed activation of the AT2R in addition to the inhibition of the AT1R. Within the context of AD, modulation of AT2R signaling could improve cognitive performance not only through its action on blood flow/brain microcirculation but also through more specific effects on neurons. This review summarizes the current state of knowledge and potential therapeutic relevance of central actions of this enigmatic receptor. In particular, we highlight the possibility that selective AT2R activation by non-peptide and highly selective agonists, acting on neuronal plasticity, could represent new pharmacological tools that may help improve impaired cognitive performance in AD and other neurological cognitive disorders.
Frontiers in Endocrinology 08/2011; 2:17. DOI:10.3389/fendo.2011.00017
"Fig. 1 presents a schematic overview of the investigated AT 2 receptor residues and suggested Ang II–AT 2 receptor contact points. We have previously derived models of the binding mode of several constrained pseudopeptide Ang II analogues to the AT 2 receptor using a ligand-based approach    . In the present study we aim to explore the ligand binding mode of both the pseudopeptides and the native ligand in the environment of the receptor. "
[Show abstract][Hide abstract] ABSTRACT: The 3D model of the AT2 receptor has been built employing homology to the transmembrane domain of rhodopsin and a novel build-up procedure for restoring the extracellular loops. By docking a model peptide of angiotensin II in the AT2 receptor model two plausible binding modes were identified. These binding modes were in agreement with most of the suggested ligand-receptor contact points reported in the literature. Eight active and one inactive pseudopeptide angiotensin II analogue were also docked in the receptor and four of the active pseudopeptides were found to mimic the binding mode of angiotensin II. An alternative binding mode for the other four active pseudopeptides was found.
Journal of Molecular Graphics and Modelling 03/2008; 26(6):991-1003. DOI:10.1016/j.jmgm.2007.08.005 · 1.72 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Two 1,3,5-trisubstituted aromatic scaffolds intended to serve as gamma-turn mimetics have been synthesized and incorporated in five pseudopeptide analogues of angiotensin II (Asp-Arg-Val-Tyr-Ile-His-Pro-Phe), replacing Val-Tyr-Ile, Val-Tyr, or Tyr-Ile. All the tested compounds exhibited nanomolar affinity for the AT2 receptor with the best compound (3) having a K(i) of 1.85 nM. Four pseudopeptides were AT2 selective, while one (5) also exhibited good affinity for the AT1 receptor (K(i) = 30.3 nM). This pseudopeptide exerted full agonistic activity in an AT2 receptor induced neurite outgrowth assay but displayed no agonistic effect in an AT1 receptor functional assay. Molecular modeling, using the program DISCOtech, showed that the high-affinity ligands could interact similarly with the AT2 receptor as other ligands with high affinity for this receptor. A tentative agonist model is proposed for AT2 receptor activation by angiotensin II analogues. We conclude that the 1,3,5-trisubstituted benzene rings can be conveniently prepared and are suitable as gamma-turn mimics.
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