| 1. |
- Hallberg, Mathias, 1971-, et al.
(author)
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Angiotensin Peptides as AT2 Receptor Agonists
- 2017
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In: Current protein and peptide science. - : Bentham Science Publishers Ltd.. - 1389-2037 .- 1875-5550. ; 18:8, s. 809-818
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Research review (peer-reviewed)abstract
- In 2004, the first nonpeptide selective angiotensin II type 2 receptor (AT2R) agonist was reported. This nonpeptide (C21), which, exerts anti-inflammatory and antifibrotic actions in vivo, has been extensively explored and is currently in clinical trials. Subsequently, a large number of related drug-like AT2R agonists have been disclosed. Reviews that summarize known structure-activity relationships (SAR) of nonpeptide AT2R agonists have recently appeared in the literature; however, very few reviews discuss the role of angiotensin peptides as AT2R agonists. Furthermore, to date, there have been no reports focusing on the medicinal chemistry perspective of peptide AT2R agonists. In the present review, reports on linear and conformationally constrained Ang II analogues, with a focus on AT2R selective ligands that are proven to act as agonists at the AT2 receptor are summarized. The impact of truncations and macrocyclizations of Ang II analogues and of incorporation of scaffolds that mimic secondary structures into Ang II related peptides is highlighted. A survey of the efforts to transform the nonselective octapeptide Ang II to more drug-like selective AT2R agonists is presented. The relationship between the structures of the AT2R agonists and their affinity to the AT2R is briefly discussed and common pharmacophore elements of AT2R selective Ang II peptide analogues and selective nonpeptide AT2R agonists are compared.
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| 2. |
- Hallberg, Mathias, 1971-, et al.
(author)
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Small-molecule AT2 receptor agonists
- 2018
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In: Medicinal research reviews (Print). - : John Wiley & Sons. - 0198-6325 .- 1098-1128. ; 38:2, s. 602-624
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Research review (peer-reviewed)abstract
- The discovery of the first selective, small-molecule ATR receptor (AT2R) agonist compound 21 (C21) (8) that is now extensively studied in a large variety of in vitro and in vivo models is described. The sulfonylcarbamate derivative 8, encompassing a phenylthiofen scaffold is the drug-like agonist with the highest affinity for the AT2R reported to date (K-i = 0.4 nM). Structure-activity relationships (SAR), regarding different biaryl scaffolds and functional groups attached to these scaffolds and with a particular focus on the impact of various para substituents displacing the methylene imidazole group of 8, are discussed. Furthermore, the consequences of migration of the methylene imidazole group and presumed structural requirements for ligands that are aimed as AT2R agonists (e.g. 8) or AT2R antagonists (e.g. 9), respectively, are briefly addressed. A summary of the pharmacological actions of C21 (8) is also presented.
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| 3. |
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| 4. |
- Reddy Vanga, Sudarsana, et al.
(author)
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Structural Basis of Inhibition of Human Insulin-Regulated Aminopeptidase (IRAP) by Aryl Sulfonamides
- 2018
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In: ACS Omega. - : AMER CHEMICAL SOC. - 2470-1343. ; 3:4, s. 4509-4521
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Journal article (peer-reviewed)abstract
- The insulin-regulated aminopeptidase (IRAP) is a membrane-bound zinc metallopeptidase with many important regulatory functions. It has been demonstrated that inhibition of IRAP by angiotensin IV (Ang IV) and other peptides, as well as more druglike inhibitors, improves cognition in several rodent models. We recently reported a series of aryl sulfonamides as small-molecule IRAP inhibitors and a promising scaffold for pharmacological intervention. We have now expanded with a number of derivatives, report their stability in liver microsomes, and characterize the activity of the whole series in a new assay performed on recombinant human IRAP. Several compounds, such as the new fluorinated derivative 29, present submicromolar affinity and high metabolic stability. Starting from the two binding modes previously proposed for the sulfonamide scaffold, we systematically performed molecular dynamics simulations and binding affinity estimation with the linear interaction energy method for the full compound series. The significant agreement with experimental affinities suggests one of the binding modes, which was further confirmed by the excellent correlation for binding affinity differences between the selected pair of compounds obtained by rigorous free energy perturbation calculations. The new experimental data and the computationally derived structure-activity relationship of the sulfonamide series provide valuable information for further lead optimization of novel IRAP inhibitors.
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| 5. |
- Wallinder, Charlotta, et al.
(author)
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High affinity rigidified AT(2) receptor ligands with indane scaffolds
- 2019
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In: MedChemComm. - : ROYAL SOC CHEMISTRY. - 2040-2503 .- 2040-2511. ; 10:12, s. 2146-2160
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Journal article (peer-reviewed)abstract
- Rigidification of the isobutyl side chain of drug-like AT(2) receptor agonists and antagonists that are structurally related to the first reported selective AT(2) receptor agonist 1 (C21) delivered bioactive indane derivatives. Four enantiomer pairs were synthesized and the enantiomers were isolated in an optical purity >99%. The enantiomers 7a, 7b, 8a, 8b, 9a, 9b, 10a and 10b bind to the AT(2) receptor with moderate (K-i = 54-223 nM) to high affinity (K-i = 2.2-7.0 nM). The enantiomer with positive optical rotation (+) exhibited the highest affinity at the receptor. The indane derivatives 7b and 10a are among the most potent AT(2) receptor antagonists reported so far. As illustrated by the enantiomer pairs 7a/b and 10a/b, an alteration at the stereogenic center has a pronounced impact on the activation process of the AT(2) receptor, and can convert agonists to antagonists and vice versa.
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| 6. |
- Wallinder, Charlotta, et al.
(author)
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Interconversion of Functional Activity by Minor Structural Alterations in Nonpeptide AT2 Receptor Ligands
- 2015
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In: ACS Medicinal Chemistry Letters. - : American Chemical Society (ACS). - 1948-5875. ; 6:2, s. 178-182
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Journal article (peer-reviewed)abstract
- Migration of the methylene imidazole side chain in the first reported selective drug-like AT, receptor agonist C21/M024 (1) delivered the AT, receptor antagonist C38/M132 (2). We now report that the AT, receptor antagonist compound 4, a biphenyl derivative that is structurally related to 2, is transformed to the agonist 6 by migration of the isobutyl group. The importance of the relative position of the methylene imidazole and the isobutyl substituent is highlighted herein.
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| 7. |
- Almgren, Magnus, 1972, et al.
(author)
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RICS-el : Building a national testbed for research and training on SCADA security (short paper)
- 2019
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In: Lect. Notes Comput. Sci.. - Cham : Springer Nature. ; 11260 LNCS, s. 219-225, s. 219-225
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Conference paper (peer-reviewed)abstract
- Trends show that cyber attacks targeting critical infrastructures are increasing, but security research for protecting such systems are challenging. There is a gap between the somewhat simplified models researchers at universities can sustain contra the complex systems at infrastructure owners that seldom can be used for direct research. There is also a lack of common datasets for research benchmarking. This paper presents a national experimental testbed for security research within supervisory control and data acquisition systems (SCADA), accessible for both research training and experiments. The virtualized testbed has been designed and implemented with both vendor experts and security researchers to balance the goals of realism with specific research needs. It includes a real SCADA product for energy management, a number of network zones, substation nodes, and a simulated power system. This environment enables creation of scenarios similar to real world utility scenarios, attack generation, development of defence mechanisms, and perhaps just as important: generating open datasets for comparative research evaluation.
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| 8. |
- Brolin, Erika, et al.
(author)
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Chronic administration of morphine using mini-osmotic pumps affects spatial memory in the male rat
- 2018
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In: Pharmacology, Biochemistry and Behavior. - : Elsevier BV. - 0091-3057 .- 1873-5177. ; 167, s. 1-8
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Journal article (peer-reviewed)abstract
- The use of opioid analgesics to treat non-cancer pain has increased over the years. Many chronic pain patients suffer from numerous adverse effects, such as reduced quality of life, development of dependence, and cognitive impairments. Cognitive processes are regulated by several systems, one of which involves growth hormone (GH) and its secondary mediator insulin-like growth factor-1 (IGF-1), but also glutamatergic transmission, including receptors such as the N-methyl-D-aspartate (NMDA)-receptor complex. In the laboratory, repeated injections are commonly used to establish animal models of long-term or chronic drug exposure. However, in the present study, we aimed to mimic a more human dose regimen using constant drug delivery provided by mini-osmotic pumps implanted subcutaneously in male Sprague Dawley rats. After developing opioid tolerance the cognitive function of rats was studied. Spatial learning and memory capabilities were evaluated using the rat Morris water maze (MWM). Moreover, gene expression related to the GH/IGF-1-axis and the NMDA-receptor system was analyzed using quantitative PCR (qPCR) and plasma levels of IGF-1 were assessed using the ELISA technique. Our results demonstrate that rats exposed to morphine for 27 days display memory impairments in the MWM probe trial. However, the behavioral effects of chronic morphine treatment were not accompanied by any significant differences in terms of mRNA expression or IGF-1 plasma concentration. The animal model used in this study provides a simple and suitable way to investigate the behavioral and neurochemical effects of chronic opioid treatment similar to the exposure seen in human pain patients.
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| 9. |
- Brolin, Erika, 1984-
(author)
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Growth hormone in the brain : Focus on cognitive function
- 2017
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Doctoral thesis (other academic/artistic)abstract
- Cognitive impairments are an increasing health problem worldwide. In the developed countries, the average life expectancy has dramatically increased over the last decades, and with an elderly population more cases of cognitive impairments appear. Age, genetics, and different medical conditions such as diabetes mellitus, and substance use disorders may all contribute to declined cognitive ability. Physiological functions also decrease with increasing age, as does the activity of the growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis. Interestingly, both GH and IGF-1 are recognized for their neuroprotective effects and cognitive enhancement. The overall aim of this thesis was to investigate the impact of the somatotrophic axis (i.e. GH/IGF-1 axis) in rodents with cognitive deficiencies induced by diabetes or long-term drug exposure. For the first time cognitive impairments were characterized in diabetic mice using a spatial learning and memory task called the Barnes maze (BM). In diabetic mice, impaired learning in the BM was associated with decreased expression of the GH receptor (GHR) in the frontal cortex, a region important for e.g. working memory. Treatment with GH reversed certain cognitive impairments seen in diabetic animals. In rats treated with gamma-hydroxybutyrate (GHB), a significant decrease of Igf1 mRNA expression in the frontal cortex was observed. This observation may explain the impaired cognitive function previously seen following GHB administration. Furthermore, rats exposed to chronic morphine delivered in mini-osmotic pumps displayed memory impairments in the Morris water maze (MWM), an effect that seems to be associated with the composition of the N-methyl-d-aspartate (NMDA) receptor complex in the frontal cortex. In conclusion, the result strengthens the evidence for GH being a cognitive enhancer. Moreover, the result within this thesis identifies the frontal cortex as an important brain region, where gene expression related to the somatotrophic system is affected in rodents with cognitive impairments. The thesis especially emphasizes the importance of the local somatotrophic system in the brain with regard to cognitive function.
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| 10. |
- Brolin, Erika, et al.
(author)
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The mRNA expression of insulin-like growth factor-1 (Igf1) is decreased in the rat frontal cortex following gamma-hydroxybutyrate (GHB) administration
- 2017
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In: Neuroscience Letters. - : Elsevier BV. - 0304-3940 .- 1872-7972. ; 646, s. 15-20
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Journal article (peer-reviewed)abstract
- In recent years, growth hormone (GH), together with its secondary mediators insulin-like growth factor-1 (IGF-1) and insulin-like growth factor-2 (IGF-2), have been highlighted for their beneficial effects in the central nervous system (CNS), in particular as cognitive enhancers. Cognitive processes, such as learning and memory, are known to be impaired in individuals suffering from substance abuse. In the present study, we investigated the effect of gamma-hydroxybuturate (GHB), an illicit drug used for its sedating and euphoric properties, on genes associated with the somatotrophic axis in regions of the brain important for cognitive function. Sprague Dawley rats (n =36) were divided into three groups and administered either saline, GHB 50 mg/kg or GHB 300 mg/kg orally for seven days. The levels of Ghr, Igf1 and Igf2 gene transcripts were analyzed using qPCR in brain regions involved in cognition and dependence. The levels of IGF-1 in blood plasma were also determined using ELISA. The results demonstrated a significant down-regulation of Igf1 mRNA expression in the frontal cortex in high-dose treated rats. Moreover, a significant correlation between Igf1 and Ghr mRNA expression was found in the hippocampus, the frontal cortex, and the caudate putamen, indicating local regulation of the GH/IGF-1 axis. To summarize, the current study concludes that chronic GHB treatment influences gene expression of Ghr and Igf1 in brain regions involved in cognitive function.
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