umu.sePublications
Change search
Link to record
Permanent link

Direct link
BETA
Svensson, Mona
Publications (10 of 10) Show all publications
Cheng, R., Mori, W., Ma, L., Alhouayek, M., Hatori, A., Zhang, Y., . . . Liang, S. H. (2018). In Vitro and in Vivo Evaluation of C-11-Labeled Azetidinecarboxylates for Imaging Monoacylglycerol Lipase by PET Imaging Studies. Journal of Medicinal Chemistry, 61(6), 2278-2291
Open this publication in new window or tab >>In Vitro and in Vivo Evaluation of C-11-Labeled Azetidinecarboxylates for Imaging Monoacylglycerol Lipase by PET Imaging Studies
Show others...
2018 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 61, no 6, p. 2278-2291Article in journal (Refereed) Published
Abstract [en]

Monoacylglycerol lipase (MAGL) is the principle enzyme for metabolizing endogenous cannabinoid ligand 2-arachidonoyglycerol (2-AG). Blockade of MAGL increases 2-AG levels, resulting in subsequent activation of the endocannabinoid system, and has emerged as a novel therapeutic strategy to treat drug addiction, inflammation, and neurodegenerative diseases. Herein we report a new series of MAGL inhibitors, which were radiolabeled by site-specific labeling technologies, including C-11-carbonylation and spirocyclic iodonium ylide (SCIDY) radio fluorination. The lead compound [C-11]10 (MAGL-0519) demonstrated high specific binding and selectivity in vitro and in vivo. We also observed unexpected washout kinetics with these irreversible radiotracers, in which in vivo evidence for turnover of the covalent residue was unveiled between MAGL and azetidine carboxylates. This work may lead to new directions for drug discovery and PET tracer development based on azetidine carboxylate inhibitor scaffold.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2018
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:umu:diva-146565 (URN)10.1021/acs.jmedchem.7b01400 (DOI)000428356600007 ()29481079 (PubMedID)
Available from: 2018-05-16 Created: 2018-05-16 Last updated: 2018-06-09Bibliographically approved
Sunduru, N., Svensson, M., Cipriano, M., Marwaha, S., Andersson, D. C., Svensson, R., . . . Elofsson, M. (2017). N-aryl 2-aryloxyacetamides as a new class of fatty acid amide hydrolase (FAAH) inhibitors. Journal of enzyme inhibition and medicinal chemistry (Print), 32(1), 513-521
Open this publication in new window or tab >>N-aryl 2-aryloxyacetamides as a new class of fatty acid amide hydrolase (FAAH) inhibitors
Show others...
2017 (English)In: Journal of enzyme inhibition and medicinal chemistry (Print), ISSN 1475-6366, E-ISSN 1475-6374, Vol. 32, no 1, p. 513-521Article in journal (Refereed) Published
Abstract [en]

Fatty acid amide hydrolase (FAAH) is a promising target for the development of drugs to treat neurological diseases. In search of new FAAH inhibitors, we identified 2-(4-cyclohexylphenoxy)-N-(3-(oxazolo[4,5-b] pyri-din-2-yl) phenyl) acetamide, 4g, with an IC50 of 2.6 mu M as a chemical starting point for the development of potent FAAH inhibitors. Preliminary hit-to-lead optimisation resulted in 2-(4-phenylphenoxy)-N-(3-(oxazolo[4,5-b] pyridin-2-yl)phenyl) acetamide, 4i, with an IC50 of 0.35 mu M.

Keywords
Fatty acid amide hydrolase inhibitors, endocannabinoid system, oxazolo[4, 5-b]pyridine anilines, 1H- idazo[4, 5-b]pyridine anilines
National Category
Medicinal Chemistry Neurosciences
Identifiers
urn:nbn:se:umu:diva-131874 (URN)10.1080/14756366.2016.1265520 (DOI)000392591100045 ()28114819 (PubMedID)
Available from: 2017-02-24 Created: 2017-02-24 Last updated: 2018-06-09Bibliographically approved
Deplano, A., Morgillo, C. M., Demurtas, M., Björklund, E., Cipriano, M., Svensson, M., . . . Onnis, V. (2017). Novel propanamides as fatty acid amide hydrolase inhibitors. European Journal of Medicinal Chemistry, 136, 523-542
Open this publication in new window or tab >>Novel propanamides as fatty acid amide hydrolase inhibitors
Show others...
2017 (English)In: European Journal of Medicinal Chemistry, ISSN 0223-5234, E-ISSN 1768-3254, Vol. 136, p. 523-542Article in journal (Refereed) Published
Abstract [en]

Fatty acid amide hydrolase (FAAH) has a key role in the control of the cannabinoid signaling, through the hydrolysis of the endocannabinoids anandamide and in some tissues 2-arachidonoylglycerol. FAAH inhibition represents a promising strategy to activate the cannabinoid system, since it does not result in the psychotropic and peripheral side effects characterizing the agonists of the cannabinoid receptors. Here we present the discovery of a novel class of profen derivatives, the N-(heteroary1)-2-(4(2-(trifluoromethyl)pyridin-4-y0amino)phenyl)propanamides, as FAAH inhibitors. Enzymatic assays showed potencies toward FAAH ranging from nanomolar to micromolar range, and the most compounds lack activity toward the two isoforms of cyclooxygenase. Extensive structure-activity studies and the definition of the binding mode for the lead compound of the series are also presented. Kinetic assays in rat and mouse FAAH on selected compounds of the series demonstrated that slight modifications of the chemical structure could influence the binding mode and give rise to competitive (TPA1) or noncompetitive (TPA14) inhibition modes.

Place, publisher, year, edition, pages
Elsevier, 2017
Keywords
FAAH inhibitors, Heteroaryl propanamides, Fatty acid amide hydrolase, Endocannabinoids, Anandamide
National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:umu:diva-137605 (URN)10.1016/j.ejmech.2017.05.033 (DOI)000403993500045 ()28535469 (PubMedID)
Available from: 2017-07-10 Created: 2017-07-10 Last updated: 2018-06-09Bibliographically approved
Gouveia-Figueira, S., Karlsson, J., Deplano, A., Hashemian, S., Svensson, M., Fredriksson Sundbom, M., . . . Fowler, C. J. (2015). Characterisation of (R)-2-(2-Fluorobiphenyl-4-yl)-N-(3-Methylpyridin-2-yl)Propanamide as a Dual Fatty Acid Amide Hydrolase: Cyclooxygenase Inhibitor. PLoS ONE, 10(9), Article ID e0139212.
Open this publication in new window or tab >>Characterisation of (R)-2-(2-Fluorobiphenyl-4-yl)-N-(3-Methylpyridin-2-yl)Propanamide as a Dual Fatty Acid Amide Hydrolase: Cyclooxygenase Inhibitor
Show others...
2015 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 9, article id e0139212Article in journal (Refereed) Published
Abstract [en]

Background Increased endocannabinoid tonus by dual-action fatty acid amide hydrolase (FAAH) and substrate selective cyclooxygenase (COX-2) inhibitors is a promising approach for pain-relief. One such compound with this profile is 2-(2-fluorobiphenyl-4-yl)-N-(3-methylpyridin-2-yl)propanamide (Flu-AM1). These activities are shown by Flu-AM1 racemate, but it is not known whether its two single enantiomers behave differently, as is the case towards COX-2 for the parent flurbiprofen enantiomers. Further, the effects of the compound upon COX-2-derived lipids in intact cells are not known. Methodology/Principal Findings COX inhibition was determined using an oxygraphic method with arachidonic acid and 2-arachidonoylglycerol (2-AG) as substrates. FAAH was assayed in mouse brain homogenates using anandamide (AEA) as substrate. Lipidomic analysis was conducted in unstimulated and lipopolysaccharide + interferon gamma-stimulated RAW 264.7 macrophage cells. Both enantiomers inhibited COX-2 in a substrate-selective and time-dependent manner, with IC50 values in the absence of a preincubation phase of: (R)-Flu-AM1, COX-1 (arachidonic acid) 6 mu M; COX-2 (arachidonic acid) 20 mu M; COX-2 (2-AG) 1 mu M; (S)-Flu-AM1, COX-1 (arachidonic acid) 3 mu M; COX-2 (arachidonic acid) 10 mu M; COX-2 (2-AG) 0.7 mu M. The compounds showed no enantiomeric selectivity in their FAAH inhibitory properties. (R)-Flu-AM1 (10 mu M) greatly inhibited the production of prostaglandin D2 and E2 in both unstimulated and lipopolysaccharide + interferon.-stimulated RAW 264.7 macrophage cells. Levels of 2-AG were not affected either by (R)-Flu-AM1 or by 10 mu M flurbiprofen, either alone or in combination with the FAAH inhibitor URB597 (1 mu M). Conclusions/Significance Both enantiomers of Flu-AM1 are more potent inhibitors of 2-AG compared to arachidonic acid oxygenation by COX-2. Inhibition of COX in lipopolysaccharide + interferon.-stimulated RAW 264.7 cells is insufficient to affect 2-AG levels despite the large induction of COX-2 produced by this treatment.

National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:umu:diva-110569 (URN)10.1371/journal.pone.0139212 (DOI)000361800700192 ()26406890 (PubMedID)
Available from: 2015-11-06 Created: 2015-10-23 Last updated: 2018-06-07Bibliographically approved
Karlsson, J., Morgillo, C. M., Deplano, A., Smaldone, G., Pedone, E., Javier Luque, F., . . . Fowler, C. J. (2015). Interaction of the N-(3-Methylpyridin-2-yl) amide Derivatives of Flurbiprofen and Ibuprofen with FAAH: Enantiomeric Selectivity and Binding Mode. PLoS ONE, 10(11), Article ID e0142711.
Open this publication in new window or tab >>Interaction of the N-(3-Methylpyridin-2-yl) amide Derivatives of Flurbiprofen and Ibuprofen with FAAH: Enantiomeric Selectivity and Binding Mode
Show others...
2015 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 11, article id e0142711Article in journal (Refereed) Published
Abstract [en]

Background Combined fatty acid amide hydrolase (FAAH) and cyclooxygenase (COX) inhibition is a promising approach for pain-relief. The Flu-AM1 and Ibu-AM5 derivatives of flurbiprofen and ibuprofen retain similar COX-inhibitory properties and are more potent inhibitors of FAAH than the parent compounds. However, little is known as to the nature of their interaction with FAAH, or to the importance of their chirality. This has been explored here. Methodology/Principal Findings FAAH inhibitory activity was measured in rat brain homogenates and in lysates expressing either wild-type or FAAH(T488A)-mutated enzyme. Molecular modelling was undertaken using both docking and molecular dynamics. The (R)-and (S)-enantiomers of Flu-AM1 inhibited rat FAAH with similar potencies (IC50 values of 0.74 and 0.99 mu M, respectively), whereas the (S)-enantiomer of Ibu-AM5 (IC50 0.59 mu M) was more potent than the (R)-enantiomer (IC50 5.7 mu M). Multiple inhibition experiments indicated that both (R)-Flu-AM1 and (S)-Ibu-AM5 inhibited FAAH in a manner mutually exclusive to carprofen. Computational studies indicated that the binding site for the Flu-AM1 and Ibu-AM5 enantiomers was located between the acyl chain binding channel and the membrane access channel, in a site overlapping the carprofen binding site, and showed a binding mode in line with that proposed for carprofen and other non-covalent ligands. The potency of (R)-Flu-AM1 was lower towards lysates expressing FAAH mutated at the proposed carprofen binding area than in lysates expressing wild-type FAAH. Conclusions/Significance The study provides kinetic and structural evidence that the enantiomers of Flu-AM1 and Ibu-AM5 bind in the substrate channel of FAAH. This information will be useful in aiding the design of novel dual-action FAAH: COX inhibitors.

National Category
Medicinal Chemistry Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-114918 (URN)10.1371/journal.pone.0142711 (DOI)000367628500049 ()
Available from: 2016-03-04 Created: 2016-01-29 Last updated: 2018-06-07Bibliographically approved
Burström, L., Björ, B., Carlsson, D., Hjalmarsson, U., Nilsson, T., Rödin, I., . . . Wahlström, J. (2014). Hälsoundersökning bland arbetande inom gruvnäring i Barentsregionen: Deskriptiva data från basenkäten, Aitik Boliden november 2012. Umeå: Umeå universitet ; Västerbottens läns landsting
Open this publication in new window or tab >>Hälsoundersökning bland arbetande inom gruvnäring i Barentsregionen: Deskriptiva data från basenkäten, Aitik Boliden november 2012
Show others...
2014 (Swedish)Report (Other academic)
Place, publisher, year, edition, pages
Umeå: Umeå universitet ; Västerbottens läns landsting, 2014. p. 17
Series
Yrkes- och miljömedicin i Umeå rapporterar, ISSN 1654-7314 ; 2014:6
National Category
Occupational Health and Environmental Health
Identifiers
urn:nbn:se:umu:diva-102919 (URN)
Projects
MineHealth
Available from: 2015-05-11 Created: 2015-05-11 Last updated: 2018-06-07Bibliographically approved
Liljelind, I., Svensson, M. & Wahlström, J. (2014). Utvärdering av en mätmetod för objektiv skattning av exponeringstiden vid hand-arm-vibrationer. Umeå: Institutionen för folkhälsa och klinisk medicin
Open this publication in new window or tab >>Utvärdering av en mätmetod för objektiv skattning av exponeringstiden vid hand-arm-vibrationer
2014 (Swedish)Report (Other academic)
Place, publisher, year, edition, pages
Umeå: Institutionen för folkhälsa och klinisk medicin, 2014. p. 13
Series
Yrkes- och miljömedicin i Umeå rapporterar, ISSN 1654-7314 ; 2014:1
National Category
Occupational Health and Environmental Health
Identifiers
urn:nbn:se:umu:diva-86283 (URN)
Available from: 2014-02-21 Created: 2014-02-21 Last updated: 2018-06-08Bibliographically approved
Nordberg, G. F., Lundström, N.-G., Forsberg, B., Hagenbjörk-Gustafsson, A., Lagerkvist, B.-S. J., Nilsson, J., . . . Eriksson, K. (2012). Lung function in volunteers before and after exposure to trichloramine in indoor pool environments and asthma in a cohort of pool workers. BMJ Open, 2(5), e000973
Open this publication in new window or tab >>Lung function in volunteers before and after exposure to trichloramine in indoor pool environments and asthma in a cohort of pool workers
Show others...
2012 (English)In: BMJ Open, ISSN 2044-6055, E-ISSN 2044-6055, Vol. 2, no 5, p. e000973-Article in journal (Refereed) Published
Abstract [en]

OBJECTIVES: Exposure to trichloramine (NCl(3)) in indoor swimming-pool environments is known to cause mucous membrane irritation, but if it gives rise to changes in lung function or asthma in adults is not known. (1) We determined lung function in volunteers before and after exposure to indoor pool environments. (2) We studied the occurrence of respiratory symptoms and asthma in a cohort of pool workers.

DESIGN/METHODS/PARTICIPANTS: (1) We studied two groups of volunteers, 37 previously non-exposed healthy persons and 14 pool workers, who performed exercise for 2 h in an indoor pool environment. NCl(3) in air was measured during pool exposures and in 10 other pool environments. Filtered air exposures were used as controls. Lung function and biomarkers of pulmonary epithelial integrity were measured before and after exposure. (2) We mailed a questionnaire to 1741 persons who indicated in the Swedish census 1990 that they worked at indoor swimming-pools.

RESULTS: (1) In previously non-exposed volunteers, statistically significant decreases in FEV(1) (forced expiratory volume) and FEV(%) (p=0.01 and 0.05, respectively) were found after exposure to pool air (0.23 mg/m(3) of NCl(3)). In pool workers, a statistically significant decrease in FEV(%) (p=0.003) was seen (but no significant change of FEV(1))(.) In the 10 other pool environments the median NCl(3) concentration was 0.18 mg/m(3). (2) Our nested case/control study in pool workers found an OR for asthma of 2.31 (95% CI 0.79 to 6.74) among those with the highest exposure. Exposure-related acute mucous membrane and respiratory symptoms were also found.

CONCLUSIONS: This is the first study in adults showing statistically significant decreases in lung function after exposure to NCl(3). An increased OR for asthma among highly exposed pool workers did not reach statistical significance, but the combined evidence supports the notion that current workroom exposures may contribute to asthma development. Further research on sensitive groups is warranted.

Place, publisher, year, edition, pages
BMJ Publishing Group, 2012
National Category
Occupational Health and Environmental Health
Identifiers
urn:nbn:se:umu:diva-60838 (URN)10.1136/bmjopen-2012-000973 (DOI)23048058 (PubMedID)
Available from: 2012-10-31 Created: 2012-10-31 Last updated: 2018-06-08Bibliographically approved
Gunnarsson, D., Svensson, M., Selstam, G. & Nordberg, G. (2004). Pronounced induction of testicular PGF2alpha and suppression of testosterone by cadmium: prevention by zinc. Toxicology, 200(1), 49-58
Open this publication in new window or tab >>Pronounced induction of testicular PGF2alpha and suppression of testosterone by cadmium: prevention by zinc
2004 (English)In: Toxicology, ISSN 0300-483X, E-ISSN 1879-3185, Vol. 200, no 1, p. 49-58Article in journal (Refereed) Published
Abstract [en]

In order to investigate the effects of cadmium (Cd) on testicular prostaglandin F(PGF) production, adult male Sprague–Dawley rats were exposed to CdCl2 by subcutaneous injections. Dose–response as well as temporal–response experiments were performed, and PGF levels were determined by radioimmunoassay (RIA). The highest cadmium dose (10 μmol/kg) caused a dramatic elevation of testicular PGF, which was established to occur 48 h after exposure. At this point of time, cadmium-treated animals displayed PGF levels 16.7 times higher than saline-injected controls. No significant differences were found with the lower doses used (1 and 5 μmol/kg). In addition, the influence of pre-treatment with zinc (Zn) was assessed. The very strong stimulatory effect on PGF synthesis (22.3-fold) detected after exposure to 20 μmol/kg cadmium, was completely absent in the group given zinc (1 mmol/kg) prior to cadmium exposure. Plasma testosterone concentrations were determined in the three experiments, and all groups with strongly elevated PGF levels showed drastically lowered concentrations of testosterone. Zinc pre-treatment abolished not only the cadmium-induced rise in PGF but also the testosterone reduction. Additionally, cadmium was found to inhibit the expression of steroidogenic acute regulatory protein (StAR), which is responsible for the rate-limiting step in steroidogenesis. The present findings establish that cadmium can cause a strong induction of testicular PGF production, which might help to explain the well-known antisteroidogenic effect of this heavy metal. Such an inhibitory effect could be due to reduced levels of StAR.

Keywords
Cadmium; Rat; Prostaglandin F2α (PGF2α); Steroidogenic acute regulatory protein (StAR); Testis; Testosterone
Identifiers
urn:nbn:se:umu:diva-3525 (URN)10.1016/j.tox.2004.03.003 (DOI)
Available from: 2008-10-09 Created: 2008-10-09 Last updated: 2018-06-09Bibliographically approved
Lagerkvist, B. J., Bernard, A., Blomberg, A., Bergström, E., Forsberg, B., Holmstrom, K., . . . Nordberg, G. (2004). Pulmonary epithelial integrity in children: relationship to ambient ozone exposure and swimming pool attendance.. Environ Health Perspect, 112(17), 1768-71
Open this publication in new window or tab >>Pulmonary epithelial integrity in children: relationship to ambient ozone exposure and swimming pool attendance.
Show others...
2004 (English)In: Environ Health Perspect, ISSN 0091-6765, Vol. 112, no 17, p. 1768-71Article in journal (Refereed) Published
Keywords
Air Pollutants/*poisoning, Child, Chlorine Compounds/poisoning, Disinfectants/poisoning, Environmental Exposure, Epithelial Cells/pathology, Female, Humans, Inflammation, Lung/immunology/pathology, Male, Oxidants; Photochemical/*poisoning, Ozone/*poisoning, Respiratory Function Tests, Swimming, Swimming Pools, Uteroglobin/*analysis
Identifiers
urn:nbn:se:umu:diva-18022 (URN)15579425 (PubMedID)
Available from: 2007-11-29 Created: 2007-11-29 Last updated: 2018-06-09Bibliographically approved
Organisations

Search in DiVA

Show all publications