| 1. |
- Sunduru, Naresh, et al.
(författare)
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N-aryl 2-aryloxyacetamides as a new class of fatty acid amide hydrolase (FAAH) inhibitors
- 2017
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Ingår i: Journal of enzyme inhibition and medicinal chemistry (Print). - : Informa UK Limited. - 1475-6366 .- 1475-6374. ; 32:1, s. 513-521
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 2. |
- Ahrné, Karin, et al.
(författare)
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Tillstånd och trender för arter och deras livsmiljöer – rödlistade arter i Sverige 2015
- 2015
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- 2015 års upplaga av den svenska rödlistan är den fjärde i ordningen. Den är baserad på IUCN:s rödlistningskriterier och revideras vart femte år. I rödlistan bedöms risken som enskilda arter av djur, växter och svampar löper att försvinna från Sverige. Bedömningen utförs av ArtDatabankens medarbetare i samverkan med över 100 externa experter, indelade i 14 expertkommittéer för olika organismgrupper. Under arbetet med 2015 års rödlista har tillstånd och trender bedömts för 21 600 arter och 1 318 lägre taxa (apomiktiska arter, underarter och varieteter), sammanlagt ca 22 900 taxa. Av de bedömda arterna klassificerades 2 029 som hotade (kategorierna CR, EN och VU) och 4 273 som rödlistade (inkluderar även kategorierna NT, RE och DD). Förhållandet mellan antalet rödlistade och antalet bedömda arter ar 19,8 %, vilket är ungefär samma värde som 2010 och 2005. I denna rapport jämförs antalet och andelen rödlistade arter mellan olika organismgrupper, biotoper, substrat och påverkansfaktorer. Texten ar indelad i en allmän del och åtta kapitel inriktade på olika landskapstyper. Landskapstyperna utgör en grov indelning av landets miljöer enligt följande kategorier: Skog, Jordbrukslandskap, Urbana miljöer, Fjäll, Våtmarker, Sötvatten, Havsstränder och Havsmiljöer. Skogen och jordbrukslandskapet är de artrikaste landskapstyperna med 1 800 respektive 1 400 arter som har en stark anknytning dit, och ytterligare flera hundra arter som förekommer där mer sporadiskt. De faktorer som påverkar flest rödlistade arter i Sverige är skogsavverkning och igenväxning, som båda utgör ett hot mot vardera ca 30 % av de rödlistade arterna. Avverkning minskar arealen av skog där naturliga strukturer och naturlig dynamik upprätthålls, och den orsakar därmed förlust av livsmiljöer. Igenväxning orsakas av ett antal faktorer, bland annat upphörande hävd (bete och slåtter), gödsling, trädplantering och brist på naturliga störningsregimer som t.ex. regelbundna översvämningar kring vattendrag och sjöar. Andra viktiga påverkansfaktorer är fiske, torrläggning av våtmarker, tillbakagång hos värdarter (främst alm och ask som drabbats av invasiva svampsjukdomar), klimatförändringar och konkurrens från invasiva arter. IUCN:s rödlisteindex beräknas för ett urval av de bedömda organismgrupperna. Rödlisteindex visar att skillnaderna mellan rödlistorna från 2000, 2005, 2010 och 2015 är små. Ett par undantag finns dock. Groddjur och stora däggdjur har fått en något förbättrad situation sedan 2000. Totalt förefaller det ändå som att trycket mot Sveriges artstock har förblivit relativt konstant under de senaste 15 åren.
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| 3. |
- Cheng, Ran, et al.
(författare)
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In Vitro and in Vivo Evaluation of C-11-Labeled Azetidinecarboxylates for Imaging Monoacylglycerol Lipase by PET Imaging Studies
- 2018
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 61:6, s. 2278-2291
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 4. |
- Deplano, Alessandro, et al.
(författare)
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Novel propanamides as fatty acid amide hydrolase inhibitors
- 2017
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Ingår i: European Journal of Medicinal Chemistry. - : Elsevier. - 0223-5234 .- 1768-3254. ; 136, s. 523-542
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 5. |
- Gouveia-Figueira, Sandra, et al.
(författare)
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Characterisation of (R)-2-(2-Fluorobiphenyl-4-yl)-N-(3-Methylpyridin-2-yl)Propanamide as a Dual Fatty Acid Amide Hydrolase : Cyclooxygenase Inhibitor
- 2015
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 10:9
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 6. |
- Karlsson, Jessica, et al.
(författare)
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Interaction of the N-(3-Methylpyridin-2-yl) amide Derivatives of Flurbiprofen and Ibuprofen with FAAH : Enantiomeric Selectivity and Binding Mode
- 2015
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 10:11
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 7. |
- Melin, Eva O., et al.
(författare)
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Affect school and script analysis versus basic body awareness therapy in the treatment of psychological symptoms in patients with diabetes and high HbA1c concentrations : two study protocols for two randomized controlled trials
- 2016
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Ingår i: Trials. - : Springer Science and Business Media LLC. - 1745-6215. ; 17
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Tidskriftsartikel (refereegranskat)abstract
- Background: Depression is linked with alexithymia, anxiety, high HbA1c concentrations, disturbances of cortisol secretion, increased prevalence of diabetes complications and all-cause mortality. The psycho-educational method 'affect school with script analysis' and the mind-body therapy 'basic body awareness treatment' will be trialled in patients with diabetes, high HbA1c concentrations and psychological symptoms. The primary outcome measure is change in symptoms of depression. Secondary outcome measures are changes in HbA1c concentrations, midnight salivary cortisol concentration, symptoms of alexithymia, anxiety, self-image measures, use of antidepressants, incidence of diabetes complications and mortality. Methods: Two studies will be performed. Study I is an open-labeled parallel-group study with a two-arm randomized controlled trial design. Patients are randomized to either affect school with script analysis or to basic body awareness treatment. According to power calculations, 64 persons are required in each intervention arm at the last follow-up session. Patients with type 1 or type 2 diabetes were recruited from one hospital diabetes outpatient clinic in 2009. The trial will be completed in 2016. Study II is a multicentre open-labeled parallel-group three-arm randomized controlled trial. Patients will be randomized to affect school with script analysis, to basic body awareness treatment, or to treatment as usual. Power calculations show that 70 persons are required in each arm at the last follow-up session. Patients with type 2 diabetes will be recruited from primary care. This study will start in 2016 and finish in 2023. For both studies, the inclusion criteria are: HbA1c concentration >= 62.5 mmol/mol; depression, alexithymia, anxiety or a negative self-image; age 18-59 years; and diabetes duration >= 1 year. The exclusion criteria are pregnancy, severe comorbidities, cognitive deficiencies or inadequate Swedish. Depression, anxiety, alexithymia and self-image are assessed using self-report instruments. HbA1c concentration, midnight salivary cortisol concentration, blood pressure, serum lipid concentrations and anthropometrics are measured. Data are collected from computerized medical records and the Swedish national diabetes and causes of death registers. Discussion: Whether the "affect school with script analysis" will reduce psychological symptoms, increase emotional awareness and improve diabetes related factors will be tried, and compared to "basic body awareness treatment" and treatment as usual.
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| 8. |
- Melin, Eva O., et al.
(författare)
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Gender, alexithymia and physical inactivity associated with abdominal obesity in type1 diabetes mellitus : a cross sectional study at a secondary care hospital diabetes clinic
- 2017
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Ingår i: BMC Obesity. - : Springer. - 2052-9538. ; 4
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Tidskriftsartikel (refereegranskat)abstract
- Background: Obesity is linked to cardiovascular diseases and increasingly common in type 1 diabetes mellitus (T1DM) since the introduction of intensified insulin therapy. Our main aim was to explore associations between obesity and depression, anxiety, alexithymia and self-image measures and to control for lifestyle variables in a sample of persons with T1DM. Secondary aims were to explore associations between abdominal and general obesity and cardiovascular complications in T1DM.Methods: Cross sectional study of 284 persons with T1DM (age 18–59 years, men 56%), consecutively recruited from one secondary care hospital diabetes clinic in Sweden. Assessments were performed with self-report instruments (Hospital Anxiety and Depression Scale, Toronto Alexithymia Scale-20 items and Structural Analysis of Social Behavior). Anthropometrics and blood samples were collected for this study and supplemented with data from the patients ’ medical records. Abdominal obesity was defined as waist circumference men/women (meters): ≥ 1.02/≥0.88, and general obesity as BMI ≥30 kg/m2 for both genders. Abdominal obesity was chosen in the analyses due to the high association with cardiovascular complications. Different explanatory logistic regression models were elaborated for the associations and calibrated and validated for goodness of fit with the data variables.Results: The prevalence of abdominal obesity was 49/284 (17%), men/women: 8%/29% (P < 0.001). Abdominal obesity was associated with women (AOR 4.9), physical inactivity (AOR 3.1), alexithymia (AOR 2.6) and age (per year) (AOR 1.04). One of the three alexithymia sub factors, “difficulty identifying feelings” (AOR 3.1), was associated with abdominal obesity. Gender analyses showed that abdominal obesity in men was associated with “difficulty identifying feelings ” (AOR 7.7), and in women with use of antidepressants (AOR 4.3) and physical inactivity (AOR 3.6). Cardiovascular complications were associated with abdominal obesity (AOR 5.2).Conclusions: Alexithymia, particularly the alexithymia subfactor “difficulty identifying feelings”, physical inactivity, and women, as well as cardiovascular complications were associated with abdominal obesity. As abdominal obesity is detrimental in diabetes due to its association with cardiovascular complications, our results suggest two risk factor treatment targets: increased emotional awareness and increased physical activity.
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| 9. |
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| 10. |
- Melin, Eva Olga, et al.
(författare)
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Lower HDL-cholesterol, a known marker of cardiovascular risk, was associated with depression in type 1 diabetes : a cross sectional study
- 2019
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Ingår i: Lipids in Health and Disease. - : BioMed Central (BMC). - 1476-511X. ; 18, s. 1-10
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Tidskriftsartikel (refereegranskat)abstract
- Background: Depression, metabolic disturbances and inflammation have been linked to cardiovascular disease and mortality. Low levels of high-density lipoprotein cholesterol (HDL-cholesterol), a known marker of cardiovascular risk, have been observed in patients with major depression in psychiatric populations. Our main aim was to explore associations between depression, antidepressants, and metabolic and inflammatory variables in patients with type 1 diabetes (T1D). A secondary aim was to explore variables associated with HDL-cholesterol. Methods: Cross-sectional design. T1D patients (n = 292, men 55%, age 18-59 years, diabetes duration >= 1 year) were consecutively recruited from one specialist diabetes clinic. Depression was defined as 8 points for Hospital Anxiety and Depression Scale-Depression sub scale. Blood samples, anthropometrics, blood pressure, and data regarding medication and life style were collected from electronic health records. Non-parametric tests, multiple logistic and linear regression analyses were performed. Results: The depression prevalence was 10 and 8% used antidepressants. Median (q(1), q(3)) HDL-cholesterol (mmol/l) was for the depressed 1.3 (1.2, 1.5) and for the non-depressed 1.6 (1.3, 1.8), p = 0.001. HDL-cholesterol levels (per mmol/l) were negatively associated with depression (Adjusted odds ratio (AOR) 0.2, p = 0.007), and the use of antidepressants was positively associated with depression (AOR 8.1, p < 0.001). No other metabolic or inflammatory variables, or life style factors, were associated with depression when adjusted for antidepressants. Abdominal obesity was associated with antidepressants in women (AOR 4.6, p = 0.029). Decreasing HDL-cholesterol levels were associated with increasing triglyceride levels (p < 0.001), increasing high-sensitive C-reactive protein (hs-CRP) levels (p = 0.021), younger age (p < 0.001), male sex (p < 0.001), and depression (p = 0.045). Conclusions: Lower HDL-cholesterol levels, known predictors of cardiovascular disease, were associated with depression in patients with T1D. The use of antidepressants was associated with abdominal obesity in women. Depression, low-grade inflammation measured as hs-CRP, higher triglycerides, male sex, and lower age were independently associated with lower HDL-cholesterol levels.
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