| 1. |
- Andappan, Murugaiah M. S., et al.
(författare)
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From the First Selective Non-Peptide AT(2) Receptor Agonist to Structurally Related Antagonists
- 2012
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 55:5, s. 2265-2278
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Tidskriftsartikel (refereegranskat)abstract
- A para substitution pattern of the phenyl ring is a characteristic feature of the first reported selective AT(2) receptor agonist M024/C21 (1) and all the nonpeptidic AT(2) receptor agonists described so far. Two series of compounds structurally related to 1 but with a meta substitution pattern have now been synthesized and biologically evaluated for their affinity to the AT(1) and AT(2) receptors. A high AT(2)/AT(1) receptor selectivity was obtained with all 41 compounds synthesized, and the majority exhibited K-i ranging from 2 to 100 nM. Five compounds were evaluated for their functional activity at the AT(2) receptor, applying a neurite outgrowth assay in NG108-15 cells.. Notably, four of the five compounds, with representatives from both series, acted as potent AT(2) receptor antagonists. These compounds were found to be considerably more effective than PD 123,319, the standard AT(2) receptor antagonist used in most laboratories. No AT(2) receptor antagonists were previously reported among the derivatives with a para substitution pattern. Hence, by a minor modification of the agonist 1 it could be transformed into the antagonist, compound 38. These compounds should serve as valuable tools in the assessment of the role of the AT(2) receptor in more complex physiological models.
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| 2. |
- Behrends, Malte, et al.
(författare)
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N-Aryl Isoleucine Derivatives as Angiotensin II AT(2) Receptor Ligands
- 2014
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Ingår i: ChemistryOpen. - : Wiley. - 2191-1363. ; 3:2, s. 65-75
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Tidskriftsartikel (refereegranskat)abstract
- A novel series of ligands for the recombinant human AT(2) receptor has been synthesized utilizing a fast and efficient palladium-catalyzed procedure for aminocarbonylation as the key reaction. Molybdenum hexacarbonyl [Mo(CO)(6)] was employed as the carbon monoxide source, and controlled microwave heating was applied. The prepared N-aryl isoleucine derivatives, encompassing a variety of amide groups attached to the aromatic system, exhibit binding affinities at best with K-i values in the low micromolar range versus the recombinant human AT(2) receptor. Some of the new nonpeptidic isoleucine derivatives may serve as starting points for further structural optimization. The presented data emphasize the importance of using human receptors in drug discovery programs.
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| 3. |
- Gallo-Payet, Nicole, et al.
(författare)
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Angiotensin II, a neuropeptide at frontier between endocrinology and neuroscience : is there a link between the angiotensin II type 2 receptor andAlzheimer’s disease?
- 2011
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Ingår i: Frontiers in Endocrinology. - : Frontiers Media SA. - 1664-2392. ; 2, s. Article 17-
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Tidskriftsartikel (refereegranskat)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.
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| 4. |
- Gallo-Payet, Nicole, et al.
(författare)
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AT2 Receptor Agonists : Exploiting the Beneficial Arm of Ang II Signaling
- 2012
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Ingår i: current hypertension reviews. - : bentham science publishers. - 1573-4021. ; 8:1, s. 47-59
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Forskningsöversikt (refereegranskat)abstract
- In the classical view, the hormone angiotensin II (Ang II) mediates its action via two major receptors, namely the Ang II type-1 receptor (AT1R) and the type-2 receptor (AT2R). Several recent reviews implicate the renin-angiotensin system (RAS) in various aspects of adipose tissue physiology and dysfunction. Research on AT2R has long been hampered by at least three potential challenges, (i) the low expression level of the AT2R in the adult, (ii) the atypical signaling pathways of AT2R and (iii) the absence of appropriate selective ligands. Indeed, apart a few exceptions, the role of the AT2R was in fact revealed by the results of simultaneous treatment with Ang II and AT1R blockers or in AT2Rdeficient mice. The first aim of this review is to summarize current paradigms concerning the role of the AT2R in adipocyte differentiation and in metabolic disorders related to insulin resistance and type 2 diabetes. Secondly, we will highlight the potential utility of selective AT2R agonists in clarifying potential roles of the AT2R in adipocyte physiology. We summarized our findings using a selective and high affinity nonpeptide ligand of the AT2R and demonstrate that AT2R is involved in adipocyte differentiation and may improve insulin sensitivity in a model of insulin resistance, in addition to increase vasodilation and reduce inflammation in adipose tissue. Thus the recent development of orally active, selective AT2R agonists should facilitate efforts to elucidate the distinct roles of the AT2R in physiology, including adipocyte physiology.
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| 5. |
- Georgsson, Jennie, et al.
(författare)
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Angiotensin II Pseudopeptides Containing 1,3,5-Trisubstituted Benzene Scaffolds with High AT2 Receptor Affinity
- 2005
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 48:21, s. 6620-6631
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Tidskriftsartikel (refereegranskat)abstract
- Two 1,3,5-trisubstituted aromatic scaffolds intended to serve as γ-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 Ki of 1.85 nM. Four pseudopeptides were AT2 selective, while one (5) also exhibited good affinity for the AT1 receptor (Ki = 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 γ-turn mimics.
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| 6. |
- Georgsson, Jennie, et al.
(författare)
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Short pseudopeptides containing turn scaffolds with high AT(2) receptor affinity
- 2006
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Ingår i: Bioorganic & Medicinal Chemistry. - : Elsevier BV. - 0968-0896 .- 1464-3391. ; 14:17, s. 5963-5972
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Tidskriftsartikel (refereegranskat)abstract
- Two pentapeptides, Ac-Tyr-Ile-His-Pro-Phe/Ile, were synthesized and shown to have angiotensin II AT(2) receptor affinity and agonistic activity. Based on these peptides, a new series of 13 pseudopeptides was synthesized via introduction of five different turn scaffolds replacing the Tyr-Ile amino acid residues. Pharmacological evaluation disclosed subnanomolar affinities for some of these compounds at the AT(2) receptor. Substitution of Phe by Ile in this series of ligands enhanced the AT(2) receptor affinity of all compounds. These results suggest that the C-terminal amino acid residues can be elaborated on to enhance the AT(2) receptor affinity in truncated Ang II analogues.
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| 7. |
- Guimond, Marie-Odile, et al.
(författare)
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Comparative functional properties of two structurally similar selective nonpeptide drug-like ligands for the angiotensin II type-2 (AT2) receptor. Effects on neurite outgrowth in NG108-15 cells
- 2012
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Ingår i: European Journal of Pharmacology - Molecular Pharmacology Section. - : Elsevier BV. - 0922-4106 .- 1872-8251. ; 699:1-3, s. 160-171
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Tidskriftsartikel (refereegranskat)abstract
- There is increasing evidence that angiotensin II (Ang II), through binding to the type 2 (AT(2)) receptor may have beneficial effects in various physiological and pathological situations. However, specific action presumably mediated by the angiotensin AT(2) receptor has been hampered by the absence of appropriate selective ligands. The aim of this study was to compare the biological properties of two related and selective drug-like nonpeptide AT(2) ligands, namely an agonist called M024 (also known as Compound 21) and a new ligand, presumably an antagonist, C38/M132, (originally called C38). Properties of the compounds were investigated in NG108-15 cells expressing angiotensin AT(2) receptor and known to develop neurite outgrowth upon Ang II stimulation. NG108-15 cells stimulated for three days with C21/M024 (0.1 or 100 nM) exhibited the same neurite outgrowth as cells stimulated with Ang II (100 nM) while co-incubation of Ang II or C21/M024 with C38/M132 (10 or 100 nM) inhibited their effects, similarly to the angiotensin AT(2) receptor antagonist, PD123319 (10 mu M). As Ang II, C21/M024 induced a Rap1-dependent activation of p42/p44(mapk) whereas preincubation of cells with C38/M132 inhibited p42/p44(mapk) and Rap1 activation induced by Ang II. Three-day treatment with C21/M024 or Ang II decreased cell number in culture, an effect that was rescued by preincubation with C38/M132. Taken together, these results indicate that the nonpeptide ligand C21/M024 is a potent angiotensin AT(2) receptor agonist while C38/M132 acts as an antagonist. These selective nonpeptide angiotensin AT(2) ligands may represent unique and long-awaited tools for the pursuit of in vivo studies.
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| 8. |
- Guimond, Marie-Odile, et al.
(författare)
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Saralasin and Sarile Are AT2 Receptor Agonists
- 2014
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Ingår i: ACS Medicinal Chemistry Letters. - : American Chemical Society (ACS). - 1948-5875. ; 5:10, s. 1129-1132
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Tidskriftsartikel (refereegranskat)abstract
- Saralasin and sarile, extensively studied over the past 40 years as angiotensin II (Ang II) receptor blockers, induce neurite outgrowth in a NG108-15 cell assay to a similar extent as the endogenous Ang II. In their undifferentiated state, these cells express mainly the AT2 receptor. The neurite outgrowth was inhibited by preincubation with the AT2 receptor selective antagonist PD 123,319, which suggests that the observed outgrowth was mediated by the AT2 receptor. Neither saralasin nor sarile reduced the neurite outgrowth induced by Ang II proving that the two octapeptides do not act as antagonists at the AT2 receptor and may be considered as AT2 receptor agonists.
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| 9. |
- Leblanc, Samuel, et al.
(författare)
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Angiotensin II Type 2 Receptor Stimulation Improves Fatty Acid Ovarian Uptake and Hyperandrogenemia in an Obese Rat Model of Polycystic Ovary Syndrome
- 2014
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Ingår i: Endocrinology. - : The Endocrine Society. - 0013-7227 .- 1945-7170. ; 155:9, s. 3684-3693
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Tidskriftsartikel (refereegranskat)abstract
- Polycystic ovary syndrome (PCOS) is mainly defined by hyperandrogenism but is also characterized by insulin resistance (IR). Studies showed that overexposure of nonadipose tissues to nonesterified fatty acids (NEFA) may explain both IR and hyperandrogenism. Recent studies indicate that treatment with an angiotensin II type 2 receptor (AT2R)-selective agonist improves diet-induced IR. We thus hypothesized that PCOS hyperandrogenism is triggered by ovarian NEFA overexposure and is improved after treatment with an AT2R agonist. Experiments were conducted in 12-week-old female JCR:LA-cp/cp rats, which are characterized by visceral obesity, IR, hyperandrogenism, and polycystic ovaries. Control JCR:LA +/? rats have a normal phenotype. Rats were treated for 8 days with saline or the selective AT2R agonist C21/M24 and then assessed for: 1) fasting testosterone, NEFA, and insulin levels; and 2) an iv 14(R,S)-[F-18]fluoro-6-thia-heptadecanoic acid test to determine NEFA ovarian tissue uptake (Km). Compared with controls, saline-treated PCOS/cp rats displayed higher insulin (100 vs 5.6 mu U/mL), testosterone (0.12 vs 0.04 nmol/L), NEFA (0.98 vs 0.48 mmol/L), and Km (20.7 vs 12.9 nmol/g.min) (all P < .0001). In PCOS/cp rats, C21/M24 did not significantly improve insulin or NEFA but normalized testosterone (P = .004) and Km(P = .009), which were strongly correlated together in all PCOS/cp rats (rho = 0.74, P = .009). In conclusion, in an obese PCOS rat model, ovarian NEFA uptake and testosterone levels are strongly associated and are both significantly reduced after short-term C21/M24 therapy. These findings provide new information on the role of NEFA in PCOS hyperandrogenemia and suggest a potential role for AT2R agonists in the treatment of PCOS.
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| 10. |
- Mahalingam, A. K., et al.
(författare)
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Selective angiotensin II AT(2) receptor agonists with reduced CYP 450 inhibition
- 2010
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Ingår i: Bioorganic & Medicinal Chemistry. - : Elsevier BV. - 0968-0896 .- 1464-3391. ; 18:12, s. 4570-4590
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Tidskriftsartikel (refereegranskat)abstract
- Structural alterations to the benzylic position of the first drug-like selective angiotensin II AT(2) receptor agonist (1) have been performed, with the emphasis to reduce the CYP 450 inhibitory property of the initial structure. The imidazole moiety, responsible for the CYP 450 inhibitory effect in 1, was replaced with various heterocycles. In addition, the modes of attachment of the heterocycles, that is, carbon versus nitrogen attachment, and introduction of carbonyl functionalities to the benzylic position have been evaluated. In all the three series, AT(2) receptor ligands with affinity in the lower nanomolar range were identified. None of the analogues, regardless of the substituents, exhibited any affinity for the AT(1) receptor. Compounds with substantially reduced inhibition of the CYP 450 enzymes were obtained. Among them the compound 60 was found to induce neurite elongation in NG 108-15 cells and served as potent AT(2) selective agonist.
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