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- Andersson, Hanna, et al.
(författare)
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Disulfide Cyclized Tripeptide Analogues of Angiotensin IV as Potent and Selective Inhibitors of Insulin-Regulated Aminopeptidase (IRAP)
- 2010
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Ingår i: Journal of Medicinal Chemistry. - 0022-2623. ; 53, s. 8059-8071
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Tidskriftsartikel (refereegranskat)abstract
- The insulin-regulated aminopeptidase (IRAP) localized in areas of the brain associated with memory and learning is emerging as a new promising therapeutic target for the treatment of memory dysfunctions. The angiotensin II metabolite angiotensin IV (Ang IV, Val1-Tyr2-Ile3-His4-Pro5-Phe6) binds with high affinity to IRAP and inhibits this aminopeptidase (Ki = 62.4 nM). Furthermore, Ang IV has been demonstrated to enhance cognition in animal models and is believed to play an important role in cognitive processes. It is herein reported that displacement of the C-terminal tripeptide His4-Pro5-Phe6 with a phenylacetic acid functionality combined with a constrained macrocyclic system in the N-terminal affords potent IRAP inhibitors that are less peptidic in character than the hexapeptide Ang IV. Configurational analysis of three pairs of diastereomeric Ang IV analogues was performed using a combination of solution NMR spectroscopic methods, Monte Carlo conformational searches, and NAMFIS calculations. The compounds encompassing l-amino acids only (4, 8, and 12) showed significantly higher bioactivity compared to their lld-epimers (5, 9, and 13). The best inhibitors in the series, compounds 8 and 12, incorporating a 13- and 14-membered disulfide ring system, respectively, and both with a β3-homotyrosine residue (β3hTyr) replacing Tyr2, exhibit Ki values of 3.3 and 5.2 nM, respectively.
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| 9. |
- Roland, P, et al.
(författare)
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A database generator for human brain imaging
- 2001
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Ingår i: TINS - Trends in Neurosciences. - 0166-2236 .- 1878-108X. ; 24:10, s. 562-564
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Tidskriftsartikel (refereegranskat)abstract
- Sharing scientific data containing complex information requires new concepts and new technology. NEUROGENERATOR is a database generator for the neuroimaging community. A database generator is a database that generates new databases. The scientists submit raw PET and fMRI data to NEUROGENERATOR, which then processes the data in a uniform way to create databases of homogenous data suitable for data sharing, met-analysis and modelling the human brain at the systems level. These databases are then distributed to the scientists.
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| 11. |
- Belew, M, et al.
(författare)
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Structure-activity studies on synthetic analogs to vasoactive peptides derived from human fibrinogen.
- 1980
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Ingår i: Biochimica et Biophysica Acta. - 0006-3002 .- 1878-2434. ; 632:1, s. 87-94
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Tidskriftsartikel (refereegranskat)abstract
- Counterparts to two vasoactive peptides previously isolated from fibrin(ogen) degraded by plasmin (EC 3.4.21.7) were synthesized by the solid phase procedure. The synthetic undecapeptide (Ser-Gln-Leu-Gln-Lys-Val-Pro-Pro-Glu-Trp-Lys) was isolated in a homogeneous state by chromatography on Sephadex G-25 and DEAE-Sepharose CL-6B and the pentapeptide (Ala-Arg-Pro-Ala-Lys) by chromatography on BioGel P-6 and column zone electrophoresis. The effect of these two peptides and of fifteen analogs to the pentapeptide on microvascular permeability in rat skin was investigated. The two synthetic counterparts were as potent as the natural peptides. With respect to the analogs, the influence of different functional groups was first studied. This was followed by attempts to minimize the active structure, induce or relieve rigidity of the peptide back-bone or otherwise accomplish modifications by a change in chirality at critical positions. Our results show that the tetrapeptide Arg-Pro-Ala-Lys has the same effect on microvascular permeability as the pentapeptide in the assay system used. Basic amino acids at both ends, as well as a proline residue adjacent to the N-terminal amino acid appear important for full or essentially full activity. On the other hand, substitution of the Ala at position 4 with several other amino acids did not result in a significant loss in biological potency.
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| 12. |
- Gerdin, Bengt, 1947-, et al.
(författare)
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Structural requirements for microvascular permeability-increasing ability of peptides. Studies on analogues of a fibrinogen pentapeptide fragment.
- 1983
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Ingår i: Biochimica et Biophysica Acta. - 0006-3002 .- 1878-2434. ; 757:3, s. 366-70
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Tidskriftsartikel (refereegranskat)abstract
- A pentapeptide, Ala-Arg-Pro-Ala-Lys, liberated from fibrinogen during plasmin-mediated fibrinolysis, was shown earlier to increase microvascular permeability in rat and human skin. Eighteen new analogues have now been synthesized in addition to the 15 previously prepared and examined for their effect on permeability. The old concept that a tetrapeptide with basic amino acids at both ends and a proline residue adjacent to the N-terminal amino acid is essential for high activity on permeability, has now been challenged. The results obtained with several of the new analogues strengthen this concept. More interestingly, however, the third amino acid, which was found in earlier studies to be less sensitive to exchange, has now been deleted as well as duplicated with only a modest loss of activity of the peptide. The chirality of the C-terminal amino acid, most surprisingly, does not seem to be crucial for peptide activity. Slightly superpotent analogues were obtained on amidation of the C-terminus. In addition, a few naturally occurring peptides, namely tuftsin, substance P, neurotensin and bradykinin, the amino acid sequences of which all exhibit characteristic features of some of our active peptide analogues were investigated in the same test system. Tuftsin displayed a potency equal to that of the pentapeptide. The other three peptides were all highly superpotent in this assay system.
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- Larhed, M, et al.
(författare)
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Rapid microwave-assisted Suzuki coupling on solid-phase
- 1996
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Ingår i: Tetrahedron Letters. - UNIV UPPSALA,CTR BIOMED,DEPT ORGAN PHARMACEUT CHEM,S-75123 UPPSALA,SWEDEN. UNIV UPPSALA,CTR BIOMED,DEPT MED & PHYSIOL CHEM,S-75123 UPPSALA,SWEDEN. : Elsevier BV. - 0040-4039 .- 1359-8562. ; 37:45, s. 8219-8222
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Tidskriftsartikel (refereegranskat)abstract
- Microwave-assisted palladium-catalysed coupling of aryl and heteroaryl boronic acids with iodo- and bromo-substituted benzoic acids, anchored to TentaGel S RAM, provided high isolated yields of coupled products after a reaction time of 3.8 minutes (45 W). Copyright (C) 1996 Elsevier Science Ltd.
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| 26. |
- Malmgren, Björn, 1942, et al.
(författare)
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Oscillatory behavior of monsoon rainfall over Sri Lanka during the late 19(th) and 20(th) centuries and its relationships to SSTs in the Indian Ocean and ENSO
- 2007
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Ingår i: Journal of Theoretical and Applied Climatology. - : Springer Science and Business Media LLC. - 0177-798X .- 1434-4483. ; 89:02-jan, s. 115-125
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Tidskriftsartikel (refereegranskat)abstract
- In this study, we have analyzed the temporal oscillations of precipitation in meso-scale zones of Sri Lanka to examine potential existence of periodic oscillatory behavior in rainfall. Only a few statistically significant cycles were identified: a 3.5-year cycle in most of central Sri Lanka during the January-March rainfall regime and a cycle of the same length in southwestern Sri Lanka during the October regime. A 2.1-year cycle marks the northeastern parts of Sri Lanka during the December/April contrast rainfall regime. This cycle is shown to be strongly related to Quasi-Biennial Oscillation. October and November rainfall are found to be coupled with ENSO fluctuations, and on average, more than 900mm more rainfall is observed per month over all stations during El Nifio than during La Nina years. Analysis of relationships between the observed meso-scale rainfall regions and the Sea Surface Temperatures (SSTs) in the Indian Ocean north of the Equator showed that the northern Indian Ocean can be divided into three particular regions based on similarity in the SST fluctuations: (a) a region with cool upwelling water, (b) non upwelling water, and (c) the Indian Ocean Warm Pool. We found that there are no statistically significant relationships between the observed SST regions in the Indian Ocean and the meso-scale precipitation patterns in Sri Lanka.
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