Umeå University's logo

umu.sePublications
Change search
Link to record
Permanent link

Direct link
Svensson, Mona
Publications (10 of 12) Show all publications
Deplano, A., Karlsson, J., Moraca, F., Svensson, M., Cristiano, C., Morgillo, C. M., . . . Onnis, V. (2021). Design, synthesis and in vitro and in vivo biological evaluation of flurbiprofen amides as new fatty acid amide hydrolase/cyclooxygenase-2 dual inhibitory potential analgesic agents. Journal of enzyme inhibition and medicinal chemistry (Print), 36(1), 940-953
Open this publication in new window or tab >>Design, synthesis and in vitro and in vivo biological evaluation of flurbiprofen amides as new fatty acid amide hydrolase/cyclooxygenase-2 dual inhibitory potential analgesic agents
Show others...
2021 (English)In: Journal of enzyme inhibition and medicinal chemistry (Print), ISSN 1475-6366, E-ISSN 1475-6374, Vol. 36, no 1, p. 940-953Article in journal (Refereed) Published
Abstract [en]

Compounds combining dual inhibitory action against FAAH and cyclooxygenase (COX) may be potentially useful analgesics. Here, we describe a novel flurbiprofen analogue, N-(3-bromopyridin-2-yl)-2-(2-fluoro-(1,1'-biphenyl)-4-yl)propanamide (Flu-AM4). The compound is a competitive, reversible inhibitor of FAAH with a Ki value of 13 nM and which inhibits COX activity in a substrate-selective manner. Molecular modelling suggested that Flu-AM4 optimally fits a hydrophobic pocket in the ACB region of FAAH, and binds to COX-2 similarly to flurbiprofen. In vivo studies indicated that at a dose of 10 mg/kg, Flu-AM4 was active in models of prolonged (formalin) and neuropathic (chronic constriction injury) pain and reduced the spinal expression of iNOS, COX-2, and NFκB in the neuropathic model. Thus, the present study identifies Flu-AM4 as a dual-action FAAH/substrate-selective COX inhibitor with anti-inflammatory and analgesic activity in animal pain models. These findings underscore the potential usefulness of such dual-action compounds.

Place, publisher, year, edition, pages
Taylor & Francis, 2021
Keywords
allodynia, cyclooxygenase, endocannabinoid, FAAH inhibition, fatty acid amide hydrolase, Flurbiprofen amides, hyperalgesia, non-steroidal anti-inflammatory drugs
National Category
Pharmacology and Toxicology Medicinal Chemistry
Identifiers
urn:nbn:se:umu:diva-183361 (URN)10.1080/14756366.2021.1875459 (DOI)000643799500001 ()33896320 (PubMedID)2-s2.0-85105117861 (Scopus ID)
Available from: 2021-05-25 Created: 2021-05-25 Last updated: 2023-09-05Bibliographically approved
Deplano, A., Karlsson, J., Svensson, M., Moraca, F., Catalanotti, B., Fowler, C. J. & Onnis, V. (2020). Exploring the fatty acid amide hydrolase and cyclooxygenase inhibitory properties of novel amide derivatives of ibuprofen. Journal of enzyme inhibition and medicinal chemistry (Print), 35(1), 815-823
Open this publication in new window or tab >>Exploring the fatty acid amide hydrolase and cyclooxygenase inhibitory properties of novel amide derivatives of ibuprofen
Show others...
2020 (English)In: Journal of enzyme inhibition and medicinal chemistry (Print), ISSN 1475-6366, E-ISSN 1475-6374, Vol. 35, no 1, p. 815-823Article in journal (Refereed) Published
Abstract [en]

Inhibition of fatty acid amide hydrolase (FAAH) reduces the gastrointestinal damage produced by non-steroidal anti-inflammatory agents such as sulindac and indomethacin in experimental animals, suggesting that a dual-action FAAH-cyclooxygenase (COX) inhibitor could have useful therapeutic properties. Here, we have investigated 12 novel amide analogues of ibuprofen as potential dual-action FAAH/COX inhibitors. N-(3-Bromopyridin-2-yl)−2-(4-isobutylphenyl)propanamide (Ibu-AM68) was found to inhibit the hydrolysis of [3H]anandamide by rat brain homogenates by a reversible, mixed-type mechanism of inhibition with a Ki value of 0.26 µM and an α value of 4.9. At a concentration of 10 µM, the compound did not inhibit the cyclooxygenation of arachidonic acid by either ovine COX-1 or human recombinant COX-2. However, this concentration of Ibu-AM68 greatly reduced the ability of the COX-2 to catalyse the cyclooxygenation of the endocannabinoid 2-arachidonoylglycerol. It is concluded that Ibu-AM68 is a dual-acting FAAH/substrate-selective COX inhibitor.

Place, publisher, year, edition, pages
Taylor & Francis, 2020
Keywords
Ibuprofen amides, FAAH inhibition, fatty acid amide hydrolase, endocannabinoid, cyclooxygenase
National Category
Pharmacology and Toxicology Medicinal Chemistry
Identifiers
urn:nbn:se:umu:diva-174734 (URN)10.1080/14756366.2020.1743283 (DOI)000560168200001 ()32200655 (PubMedID)2-s2.0-85082278965 (Scopus ID)
Available from: 2020-09-03 Created: 2020-09-03 Last updated: 2023-03-24Bibliographically approved
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)2-s2.0-85044192787 (Scopus ID)
Available from: 2018-05-16 Created: 2018-05-16 Last updated: 2023-03-24Bibliographically 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)2-s2.0-85013857480 (Scopus ID)
Available from: 2017-02-24 Created: 2017-02-24 Last updated: 2023-03-23Bibliographically 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)2-s2.0-85019575603 (Scopus ID)
Available from: 2017-07-10 Created: 2017-07-10 Last updated: 2023-03-23Bibliographically 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, 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)2-s2.0-84947261212 (Scopus ID)
Available from: 2015-11-06 Created: 2015-10-23 Last updated: 2023-03-23Bibliographically 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, 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 ()2-s2.0-84958817302 (Scopus ID)
Available from: 2016-03-04 Created: 2016-01-29 Last updated: 2023-03-23Bibliographically 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: 2022-12-21Bibliographically 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, 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)2-s2.0-84869819412 (Scopus ID)
Available from: 2012-10-31 Created: 2012-10-31 Last updated: 2024-04-05Bibliographically approved
Organisations

Search in DiVA

Show all publications