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Sävmarker, Jonas
Publications (10 of 34) Show all publications
Shariatgorji, M., Nilsson, A., Fridjonsdottir, E., Vallianatou, T., Källbäck, P., Katan, L., . . . Andrén, P. E. (2019). Comprehensive mapping of neurotransmitter networks by MALDI-MS imaging. Nature Methods, 16(10), 1021-1028
Open this publication in new window or tab >>Comprehensive mapping of neurotransmitter networks by MALDI-MS imaging
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2019 (English)In: Nature Methods, ISSN 1548-7091, E-ISSN 1548-7105, Vol. 16, no 10, p. 1021-1028Article in journal (Refereed) Published
Abstract [en]

We present a mass spectrometry imaging (MSI) approach for the comprehensive mapping of neurotransmitter networks in specific brain regions. Our fluoromethylpyridinium-based reactive matrices facilitate the covalent charge-tagging of molecules containing phenolic hydroxyl and/or primary or secondary amine groups, including dopaminergic and serotonergic neurotransmitters and their associated metabolites. These matrices improved the matrix-assisted laser desorption/ionization (MALDI)-MSI detection limit toward low-abundance neurotransmitters and facilitated the simultaneous imaging of neurotransmitters in fine structures of the brain at a lateral resolution of 10 mu m. We demonstrate strategies for the identification of unknown molecular species using the innate chemoselectivity of the reactive matrices and the unique isotopic pattern of a brominated reactive matrix. We illustrate the capabilities of the developed method on Parkinsonian brain samples from human post-mortem tissue and animal models. The direct imaging of neurotransmitter systems provides a method for exploring how various neurological diseases affect specific brain regions through neurotransmitter modulation.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2019
National Category
Analytical Chemistry
Identifiers
urn:nbn:se:uu:diva-395725 (URN)10.1038/s41592-019-0551-3 (DOI)000488225900033 ()31548706 (PubMedID)
Funder
Swedish Foundation for Strategic Research , RIF14-0078EU, FP7, Seventh Framework Programme, 607517Swedish Research Council, 2018-03320Swedish Research Council, 2018-05501Swedish Research Council, 2018-05133
Available from: 2019-10-24 Created: 2019-10-24 Last updated: 2019-10-24Bibliographically approved
Wannberg, J., Isaksson, R., Bremberg, U., Backlund, M., Sävmarker, J., Hallberg, M. & Larhed, M. (2018). A convenient transesterification method for synthesis of AT2 receptor ligands with improved stability in human liver microsomes. Bioorganic & Medicinal Chemistry Letters, 28(3), 519-522
Open this publication in new window or tab >>A convenient transesterification method for synthesis of AT2 receptor ligands with improved stability in human liver microsomes
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2018 (English)In: Bioorganic & Medicinal Chemistry Letters, ISSN 0960-894X, E-ISSN 1090-2120, Vol. 28, no 3, p. 519-522Article in journal (Refereed) Published
Abstract [en]

A series of AT2R ligands have been synthesized applying a quick, simple, and safetransesterification-type reaction whereby the sulfonyl carbamate alkyl tail ofthe selective AT2R antagonist C38 was varied. Furthermore, a limited number ofcompounds where acyl sulfonamides and sulfonyl ureas served as carboxylic acidbioisosteres were synthesized and evaluated. By reducing the size of the alkylchain of the sulfonyl carbamates, ligands 7a and 7b were identified withsignificantly improved in vitro metabolic stability in both human and mouse livermicrosomes as compared to C38 while retaining the AT2R binding affinity andAT2R/AT1R selectivity. Eight of the compounds synthesized exhibit an improvedstability in human microsomes as compared to C38.

Place, publisher, year, edition, pages
Elsevier, 2018
Keywords
AT(2)R antagonists, Angiotensin II type 2 receptor antagonists, Liver microsomes, Sulfonyl carbamates, Transesterification
National Category
Organic Chemistry Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-343592 (URN)10.1016/j.bmcl.2017.11.042 (DOI)000424285600053 ()29279275 (PubMedID)
Funder
Science for Life Laboratory - a national resource center for high-throughput molecular bioscience
Available from: 2018-02-28 Created: 2018-02-28 Last updated: 2019-04-04Bibliographically approved
Roy, T., Rydfjord, J., Sävmarker, J. & Nordeman, P. (2018). Palladium-catalyzed carbonylation of aryl bromides using microwave heating and bis[CP-Fe(II)-(CO)2] as a carbon monoxide source. Tetrahedron Letters, 59(13), 1230-1232
Open this publication in new window or tab >>Palladium-catalyzed carbonylation of aryl bromides using microwave heating and bis[CP-Fe(II)-(CO)2] as a carbon monoxide source
2018 (English)In: Tetrahedron Letters, ISSN 0040-4039, E-ISSN 1359-8562, Vol. 59, no 13, p. 1230-1232Article in journal (Refereed) Published
Abstract [en]

A palladium-catalyzed, microwave assisted carbonylative reaction is described for the synthesis of benzamides from aryl bromides and primary or secondary amines. The developed method uses bis(cyclopentadienyldicarbonyliron) as a solid source of carbon monoxide to produce a diverse set of secondary and tertiary amides in 42-82% yield.

Keywords
Palladium, Carbon monoxide, Carbonylation, CORM, Microwaves
National Category
Organic Chemistry
Research subject
Chemistry with specialization in Organic Chemistry
Identifiers
urn:nbn:se:uu:diva-355077 (URN)10.1016/j.tetlet.2018.02.035 (DOI)000428007300015 ()
Available from: 2018-06-26 Created: 2018-06-26 Last updated: 2019-06-28Bibliographically approved
Reddy Vanga, S., Sävmarker, J., Ng, L., Larhed, M., Hallberg, M., Åqvist, J., . . . Gutiérrez-de-Terán, H. (2018). Structural Basis of Inhibition of Human Insulin-Regulated Aminopeptidase (IRAP) by Aryl Sulfonamides. ACS OMEGA, 3(4), 4509-4521
Open this publication in new window or tab >>Structural Basis of Inhibition of Human Insulin-Regulated Aminopeptidase (IRAP) by Aryl Sulfonamides
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2018 (English)In: ACS OMEGA, ISSN 2470-1343, Vol. 3, no 4, p. 4509-4521Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
AMER CHEMICAL SOC, 2018
National Category
Biochemistry and Molecular Biology Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-358572 (URN)10.1021/acsomega.8b00595 (DOI)000434352800025 ()30023895 (PubMedID)
Funder
Swedish Research Council
Available from: 2018-09-17 Created: 2018-09-17 Last updated: 2019-10-16Bibliographically approved
Hallberg, M., Sävmarker, J. & Hallberg, A. (2017). Angiotensin Peptides as AT2 Receptor Agonists. Current protein and peptide science, 18(8), 809-818
Open this publication in new window or tab >>Angiotensin Peptides as AT2 Receptor Agonists
2017 (English)In: Current protein and peptide science, ISSN 1389-2037, E-ISSN 1875-5550, Vol. 18, no 8, p. 809-818Article, review/survey (Refereed) Published
Abstract [en]

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.

Keywords
Angiotensin II, AT2 receptor agonist, peptide, peptidemimetic, secondary structure mimetic, bioactive conformation
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:uu:diva-335828 (URN)10.2174/1389203718666170203150344 (DOI)000405303000003 ()28164758 (PubMedID)
Available from: 2017-12-15 Created: 2017-12-15 Last updated: 2017-12-15Bibliographically approved
Adeyemi, A., Bergman, J., Branalt, J., Sävmarker, J. & Larhed, M. (2017). Continuous Flow Synthesis under High-Temperature/High-Pressure Conditions Using a Resistively Heated Flow Reactor. Organic Process Research & Development, 21(7), 947-955
Open this publication in new window or tab >>Continuous Flow Synthesis under High-Temperature/High-Pressure Conditions Using a Resistively Heated Flow Reactor
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2017 (English)In: Organic Process Research & Development, ISSN 1083-6160, E-ISSN 1520-586X, Vol. 21, no 7, p. 947-955Article in journal (Refereed) Published
Abstract [en]

A cheap, easy-to-build, and effective resistively heated reactor for continuous flow synthesis at high temperature and pressure is herein presented. The reactor is rapidly heated directly using, an electric current and is capable of rapidly delivering temperatures and pressures up to 400 degrees C and 200 bar, respectively. High-temperature and high-pressure applications of this reactor were safely performed and demonstrated by selected transformations such as esterifications, transesterifications, and direct carboxylic acid to nitrile reactions using supercritical ethanol, methanol, and acetonitrile. Reaction temperatures were between 300 and 400 degrees C with excellent conversions and good to excellent isolated product yields. Examples of Diels-Alder reactions were also carried out at temperatures up to 300 degrees C in high yield. No additives or catalysts were used in the reactions.

Place, publisher, year, edition, pages
AMER CHEMICAL SOC, 2017
National Category
Chemical Sciences
Identifiers
urn:nbn:se:uu:diva-333407 (URN)10.1021/acs.oprd.7b00063 (DOI)000406356200003 ()
Funder
EU, FP7, Seventh Framework Programme, 607517
Available from: 2017-11-15 Created: 2017-11-15 Last updated: 2017-11-15Bibliographically approved
Kumaniaev, I., Subbotina, E., Sävmarker, J., Larhed, M., Galkin, M. V. & Samec, J. S. M. (2017). Lignin depolymerization to monophenolic compounds in a flow-through system. Green Chemistry, 19(24), 5767-5771
Open this publication in new window or tab >>Lignin depolymerization to monophenolic compounds in a flow-through system
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2017 (English)In: Green Chemistry, ISSN 1463-9262, E-ISSN 1463-9270, Vol. 19, no 24, p. 5767-5771Article in journal (Refereed) Published
Abstract [en]

A reductive lignocellulose fractionation in a flow-through system in which pulping and transfer hydrogenolysis steps were separated in time and space has been developed. Without the hydrogenolysis step or addition of trapping agents to the pulping, it is possible to obtain partially depolymerized lignin (21 wt% monophenolic compounds) that is prone to further processing. By applying a transfer hydrogenolysis step 37 wt% yield of lignin derived monophenolic compounds was obtained. Pulp generated in the process was enzymatically hydrolyzed to glucose in 87 wt% yield without prior purification.

National Category
Organic Chemistry
Identifiers
urn:nbn:se:uu:diva-339769 (URN)10.1039/c7gc02731a (DOI)000417756500003 ()
Funder
Swedish Energy Agency
Available from: 2018-02-09 Created: 2018-02-09 Last updated: 2018-02-09Bibliographically approved
Roy, T., Brandt, P., Wetzel, A., Bergman, J., Branalt, J., Sävmarker, J. & Larhed, M. (2017). Selective Synthesis of Spirooxindoles by an Intramolecular Heck-Mizoroki Reaction. Organic Letters, 19(10), 2738-2741
Open this publication in new window or tab >>Selective Synthesis of Spirooxindoles by an Intramolecular Heck-Mizoroki Reaction
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2017 (English)In: Organic Letters, ISSN 1523-7060, E-ISSN 1523-7052, Vol. 19, no 10, p. 2738-2741Article in journal (Refereed) Published
Abstract [en]

We report a highly diastereoselective synthesis of cydopentene-spirooxindole derivatives via an intramolecular Heck-Mizoroki reaction using aryl bromides as precursors. The reactions were performed under dry conditions or in a DMF-water system. This protocol can be useful to introduce several functionalities to the aromatic nucleus of the spirooxindoles. DFT calculations were performed to rationalize the high antiselectivity. A functionalized spiroproduct was transformed into a cyclic amino acid derivative.

Place, publisher, year, edition, pages
AMER CHEMICAL SOC, 2017
National Category
Organic Chemistry
Identifiers
urn:nbn:se:uu:diva-326242 (URN)10.1021/acs.orglett.7b01094 (DOI)000402023500071 ()28471686 (PubMedID)
Available from: 2017-08-10 Created: 2017-08-10 Last updated: 2017-08-10Bibliographically approved
Diwakarla, S., Nylander, E., Grönbladh, A., Reddy Vanga, S., Shamsudin Khan, Y., Gutierrez-de-Teran, H., . . . Hallberg, M. (2016). Binding to and Inhibition of Insulin-Regulated Aminopeptidase (IRAP) by Macrocyclic Disulfides Enhances Spine Density. Molecular Pharmacology, 89(4), 413-424
Open this publication in new window or tab >>Binding to and Inhibition of Insulin-Regulated Aminopeptidase (IRAP) by Macrocyclic Disulfides Enhances Spine Density
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2016 (English)In: Molecular Pharmacology, ISSN 0026-895X, E-ISSN 1521-0111, Vol. 89, no 4, p. 413-424Article in journal (Refereed) Published
Abstract [en]

Angiotensin IV (Ang IV) and related peptide analogues, as well as non-peptide inhibitors of insulin-regulated aminopeptidase (IRAP), have previously been shown to enhance memory and cognition in animal models. Furthermore, the endogenous IRAP substrates oxytocin and vasopressin are known to facilitate learning and memory. In this study, the two recently synthesized 13-membered macrocylic competitive IRAP inhibitors HA08 and HA09, which were designed to mimic the N-terminal of oxytocin and vasopressin, were assessed and compared based on their ability to bind to the IRAP active site, and alter dendritic spine density in rat hippocampal primary cultures. The binding modes of the IRAP inhibitors HA08, HA09 and of Ang IV in either the extended or γ-turn conformation at the C-terminal to human IRAP were predicted by docking and molecular dynamics (MD) simulations. The binding free energies calculated with the linear interaction energy (LIE) method, which are in excellent agreement with experimental data and simulations, have been used to explain the differences in activities of the IRAP inhibitors, both of which are structurally very similar, but differ only with regard to one stereogenic center. In addition, we show that HA08, which is 100-fold more potent than the epimer HA09, can enhance dendritic spine number and alter morphology, a process associated with memory facilitation. Therefore, HA08, one of the most potent IRAP inhibitors known today, may serve as a suitable starting point for medicinal chemistry programs aided by MD simulations aimed at discovering more drug-like cognitive enhancers acting via augmenting synaptic plasticity.

National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-275166 (URN)10.1124/mol.115.102533 (DOI)000370935700003 ()26769413 (PubMedID)
Funder
Swedish Research Council
Available from: 2016-01-31 Created: 2016-01-31 Last updated: 2019-10-16
Skillinghaug, B., Rydfjord, J., Sävmarker, J. & Larhed, M. (2016). Microwave Heated Continuous Flow Palladium(II)-Catalyzed Desulfitative Synthesis of Aryl Ketones. Organic Process Research & Development, 20(11), 2005-2011
Open this publication in new window or tab >>Microwave Heated Continuous Flow Palladium(II)-Catalyzed Desulfitative Synthesis of Aryl Ketones
2016 (English)In: Organic Process Research & Development, ISSN 1083-6160, E-ISSN 1520-586X, Vol. 20, no 11, p. 2005-2011Article in journal (Refereed) Published
Abstract [en]

A protocol for Pd(II)-catalyzed desulfitative synthesis of aryl ketones from sodium aryl sulfinates and nitriles in continuous flow has been developed. The reactions proceed with microwave heating using microwave transparent tube reactors, affording the desired aryl ketones in fair to good yields. Microwave transparent aluminum oxide reactors were identified as a safe and thermostable alternative to borosilicate glass reactors.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2016
Keywords
Heck-Type Reaction, Direct Esi-Ms, Organic-Synthesis, Sulfinic Acids, High-Speed, Chemistry, Arylation, Nitriles, Hydrogenation, Temperature
National Category
Organic Chemistry
Identifiers
urn:nbn:se:uu:diva-304719 (URN)10.1021/acs.oprd.6b00306 (DOI)000388430300017 ()
Available from: 2016-10-08 Created: 2016-10-08 Last updated: 2017-11-30Bibliographically approved
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