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  • 1.
    Cipriano, Mariateresa
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Björklund, Emmelie
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Wilson, Alan A.
    Congiu, Cenzo
    Onnis, Valentina
    Fowler, Christopher J.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Inhibition of fatty acid amide hydrolase and cyclooxygenase by the N-(3-methylpyridin-2-yl)amide derivatives of flurbiprofen and naproxen2013In: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 720, no 1-3, p. 383-390Article in journal (Refereed)
    Abstract [en]

    Inhibitors of the metabolism of the endogenous cannabinoid ligand anandamide by fatty acid amide hydrolase (FAAH) reduce the gastric damage produced by non-steroidal anti-inflammatory agents and synergise with them in experimental pain models. This motivates the design of compounds with joint FAAH/cyclooxygenase (COX) inhibitory activity. Here we present data on the N-(3-methylpyridin-2-yl) amide derivatives of flurbiprofen and naproxen (Flu-AM1 and Nap-AM1, respectively) with respect to their properties towards these two enzymes. Flu-AM1 and Nap-AM1 inhibited FAAH-catalysed hydrolysis of [H-3]anandamide by rat brain homogenates with IC50 values of 044 and 0.74 mu M. The corresponding values for flurbiprofen and naproxen were 29 and > 100 mu M, respectively. The inhibition by Flu-AM1 was reversible, mixed-type, with K-slope(i) and K-intercept(i) values of 0.21 and 1.4 mu M, respectively. Flurbiprofen and Flu-AM1 both inhibited COX in the same manner with the order of potencies COX-2 vs. 2-arachidonoylglycerol > COX-1 vs. arachidonic acid > COX-2 vs. arachidonic acid with flurbiprofen being approximately 2-3 fold more potent than Flu-AM 1 in the assays. Nap-AM1 was a less potent inhibitor of COX. Flu-AM1 at low micromolar concentrations inhibited the FAAH-driven uptake of [H-3]anandamide into RBL2H3 basophilic leukaemia cells in vitro, but did not penetrate the brain in vivo sufficiently to block the binding of [F-18]DOPP to brain FAAH. It is concluded that Flu-AM 1 is a dual-action inhibitor of FAAH and COX that may be useful in exploring the optimal balance of effects on these two enzyme systems in producing peripheral alleviation of pain and inflammation in experimental models.

  • 2.
    Cipriano, Mariateresa
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Gouveia-Figueira, Sandra
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Persson, Emma
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Nording, Malin
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Fowler, Christopher
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    The influence of monoacylglycerol lipase inhibition upon the expression of epidermal growth factor receptor in human PC-3 prostate cancer cells.2014In: BMC Research Notes, ISSN 1756-0500, E-ISSN 1756-0500, Vol. 7, p. 441-447Article in journal (Refereed)
    Abstract [en]

    Background: It has been reported that direct activation of the cannabinoid CB1 receptor in epidermal growth factor (EGR)-stimulated PC-3 prostate cancer cells results in an anti-proliferative effect accompanied by a down-regulation of EGF receptors (EGFR). In the present study, we investigated whether similar effects are seen following inhibition of the endocannabinoid hydrolytic enzyme monoacylglycerol lipase (MGL).

    Results: CB1 receptor expression levels were found to differ greatly between two experimental series conducted using PC-3 cells. The monoacylglycerol lipase inhibitor JZL184 increased levels of 2-arachidonoylglycerol in the PC-3 cells without producing changes in the levels of anandamide and related N-acylethanolamines. In the first series of experiments, JZL184 produced a small mitogenic effect for cells that had not been treated with EGF, whereas an anti-proliferative effect was seen for EGF-treated cells. An anti-proliferative effect for the EGF-treated cells was also seen with the CB receptor agonist CP55,940. In the second batch of cells, there was an interaction between JZL184 and CB1 receptor expression densities in linear regression analyses with EGFR expression as the dependent variable.

    Conclusions: Inhibition of MGL by JZL184 can affect EGFR expression. However, the use in our hands of PC-3 cells as a model to investigate the therapeutic potential of MGL inhibitors and related compounds is compromised by their variability of CB1 receptor expression.

  • 3.
    Cipriano, Mariateresa
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Häggström, Jenny
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Hammarsten, Peter
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Fowler, Christopher J
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Association between cannabinoid CB1 receptor expression and Akt signalling in prostate cancer2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 6, p. e65798-Article in journal (Refereed)
    Abstract [en]

    Background: In prostate cancer, tumour expression of cannabinoid CB1 receptors is associated with a poor prognosis. One explanation for this association comes from experiments with transfected astrocytoma cells, where a high CB receptor expression recruits the Akt signalling survival pathway. In the present study, we have investigated the association between CB1 receptor expression and the Akt pathway in a well-characterised prostate cancer tissue microarray.

    Methodology/Principal Findings: Phosphorylated Akt immunoreactivity (pAkt-IR) scores were available in the database. CB1 receptor immunoreactivity (CB1IR) was rescored from previously published data using the same scale as pAkt-IR. There was a highly significant correlation between CB1IR and pAkt-IR. Further, cases with high expression levels of both biomarkers were much more likely to have a more severe form of the disease at diagnosis than those with low expression levels. The two biomarkers had additive effects, rather than an interaction, upon disease-specific survival.

    Conclusions/Significance: The present study provides data that is consistent with the hypothesis that at a high CB1 receptor expression, the Akt signalling pathway becomes operative.

  • 4. Deplano, Alessandro
    et al.
    Cipriano, Mariateresa
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Moraca, Federica
    Novellino, Ettore
    Catalanotti, Bruno
    Fowler, Christopher J
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Onnis, Valentina
    Benzylamides and piperazinoarylamides of ibuprofen as fatty acid amide hydrolase inhibitors2019In: Journal of enzyme inhibition and medicinal chemistry (Print), ISSN 1475-6366, E-ISSN 1475-6374, Vol. 34, no 1, p. 562-576Article in journal (Refereed)
    Abstract [en]

    Fatty Acid Amide Hydrolase (FAAH) is a serine hydrolase that plays a key role in controlling endogenous levels of endocannabinoids. FAAH inhibition is considered a powerful approach to enhance the endocannabinoid signalling, and therefore it has been largely studied as a potential target for the treatment of neurological disorders such as anxiety or depression, or of inflammatory processes. We present two novel series of amide derivatives of ibuprofen designed as analogues of our reference FAAH inhibitor Ibu-AM5 to further explore its structure-activity relationships. In the new amides, the 2-methylpyridine moiety of Ibu-AM5 was substituted by benzylamino and piperazinoaryl moieties. The obtained benzylamides and piperazinoarylamides showed FAAH inhibition ranging from the low to high micromolar potency. The binding of the new amides in the active site of FAAH, estimated using the induced fit protocol, indicated arylpiperazinoamides binding the ACB channel and the cytosolic port, and benzylamides binding the ACB channel.

  • 5. Deplano, Alessandro
    et al.
    Morgillo, Carmine Marco
    Demurtas, Monica
    Björklund, Emmelie
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Cipriano, Mariateresa
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Svensson, Mona
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Hashemian, Sanaz
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Smaldone, Giovanni
    Pedone, Emilia
    Javier Luque, F.
    Cabiddu, Maria G.
    Novellino, Ettore
    Fowler, Christopher J.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Catalanotti, Bruno
    Onnis, Valentina
    Novel propanamides as fatty acid amide hydrolase inhibitors2017In: European Journal of Medicinal Chemistry, ISSN 0223-5234, E-ISSN 1768-3254, Vol. 136, p. 523-542Article in journal (Refereed)
    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.

  • 6.
    Hammarsten, Peter
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Cipriano, Mariateresa
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Josefsson, Andreas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Egevad, Lars
    Granfors, Torvald
    Fowler, Christopher J.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Phospho-Akt Immunoreactivity in Prostate Cancer: Relationship to Disease Severity and Outcome, Ki67 and Phosphorylated EGFR Expression2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 10, p. e47994-Article in journal (Refereed)
    Abstract [en]

    Background: In the present study, we have investigated the prognostic usefulness of phosphorylated Akt immunoreactivity (pAkt-IR) in prostate cancer using a well-characterised tissue microarray from men who had undergone transurethral resection due to lower urinary tract symptoms. Methodology/Principal Findings: pAkt-IR in prostate epithelial and tumour cells was assessed using a monoclonal anti-pAkt (Ser(473)) antibody. Immunoreactive intensity was determined for 282 (tumour) and 240 (non-mlignant tissue) cases. Tumour pAkt-IR scores correlated with Gleason score, tumour Ki67-IR (a marker of cell proliferation) and tumour phosphorylated epidermal growth factor receptor (pEGFR)-IR. For cases followed with expectancy, a high tumour pAkt-IR was associated with a poor disease-specific survival, and the prognostic information provided by this biomarker was additive to that provided by either (but not both) tumour pEFGR-IR or Ki67-IR. Upon division of the cases with respect to their Gleason scores, the prognostic value of pAkt-IR was seen for patients with Gleason score 8-10, but not for patients with Gleason score 6-7. Conclusions/Significance: Tumour pAkt-IR is associated with both disease severity and disease-specific survival. However, its clinical use as a biomarker is limited, since it does not provide prognostic information in patients with Gleason scores 6-7.

  • 7. Hernández-Torres, Gloria
    et al.
    Cipriano, Mariateresa
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Hedén, Erika
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Björklund, Emmelie
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Canales, Ángeles
    Zian, Debora
    Feliú, Ana
    Mecha, Miriam
    Guaza, Carmen
    Fowler, Christopher J.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Ortega-Gutiérrez, Silvia
    López-Rodríguez, María L.
    A reversible and selective inhibitor of monoacylglycerol lipase ameliorates multiple sclerosis2014In: Angewandte Chemie International Edition, ISSN 1433-7851, E-ISSN 1521-3773, Vol. 53, no 50, p. 13765-13770Article in journal (Refereed)
    Abstract [en]

    Monoacylglycerol lipase (MAGL) is the enzyme responsible for the inactivation of the endocannabinoid 2-arachidonoylglycerol (2-AG). MAGL inhibitors show analgesic and tissue-protecting effects in several disease models. However, the few efficient and selective MAGL inhibitors described to date block the enzyme irreversibly, and this can lead to pharmacological tolerance. Hence, additional classes of MAGL inhibitors are needed to validate this enzyme as a therapeutic target. Here we report a potent, selective, and reversible MAGL inhibitor (IC50=0.18M) which is active in vivo and ameliorates the clinical progression of a multiple sclerosis (MS) mouse model without inducing undesirable CB1-mediated side effects. These results support the interest in MAGL as a target for the treatment of MS.

  • 8.
    Häggström, Jenny
    et al.
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Cipriano, Mariateresa
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Plym Forshell, Linus
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Persson, Emma
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Hammarsten, Peter
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Stella, Nephi
    Fowler, Christopher J.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Potential upstream regulators of cannabinoid receptor 1 signaling in prostate cancer: A Bayesian network analysis of data from a tissue microarray2014In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 74, no 11, p. 1107-1117Article in journal (Refereed)
    Abstract [en]

    BACKGROUND The endocannabinoid system regulates cancer cell proliferation, and in prostate cancer a high cannabinoid CB1 receptor expression is associated with a poor prognosis. Down-stream mediators of CB1 receptor signaling in prostate cancer are known, but information on potential upstream regulators is lacking. RESULTS Data from a well-characterized tumor tissue microarray were used for a Bayesian network analysis using the max-min hill-climbing method. In non-malignant tissue samples, a directionality of pEGFR (the phosphorylated form of the epidermal growth factor receptor) CB1 receptors were found regardless as to whether the endocannabinoid metabolizing enzyme fatty acid amide hydrolase (FAAH) was included as a parameter. A similar result was found in the tumor tissue, but only when FAAH was included in the analysis. A second regulatory pathway, from the growth factor receptor ErbB2 FAAH was also identified in the tumor samples. Transfection of AT1 prostate cancer cells with CB1 receptors induced a sensitivity to the growth-inhibiting effects of the CB receptor agonist CP55,940. The sensitivity was not dependent upon the level of receptor expression. Thus a high CB1 receptor expression alone does not drive the cells towards a survival phenotype in the presence of a CB receptor agonist. CONCLUSIONS The data identify two potential regulators of the endocannabinoid system in prostate cancer and allow the construction of a model of a dysregulated endocannabinoid signaling network in this tumor. Further studies should be designed to test the veracity of the predictions of the network analysis in prostate cancer and other solid tumors.

  • 9. Patel, Jayendra Z.
    et al.
    Parkkari, Teija
    Laitinen, Tuomo
    Kaczor, Agnieszka A.
    Saario, Susanna M.
    Savinainen, Juha R.
    Navia-Padanius, Dina
    Cipriano, Mariateresa
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Leppanen, Jukka
    Koshevoy, Igor O.
    Poso, Antti
    Fowler, Christopher J.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Laitinen, Jarmo T.
    Nevalainen, Tapio
    Chiral 1,3,4-Oxadiazol-2-ones as Highly Selective FAAH Inhibitors2013In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 56, no 21, p. 8484-8496Article in journal (Refereed)
    Abstract [en]

    In the present study, identification of chiral 1,3,4-oxadiazol-2-ones as potent and selective FAAH inhibitors has been described. The separated enantiomers showed clear differences in the potency and selectivity toward both FAAH and MAGL. Additionally, the importance of the chirality on the inhibitory activity and selectivity was proven by the simplification approach by removing a methyl group at the 3-position of the 1,3,4-oxadiazol-2-one ring. The most potent compound of the series, the S-enantiomer of 3-(1-(4-isobutylphenyl)ethyl)-5-methoxy-1,3,4-oxadiazol-2(3H)-one (JZP-327A, Si), inhibited human recombinant FAAH (hrFAAH) in the low nanomolar range (IC50 = 11 mu M), whereas its corresponding R-enantiomer 52 showed only moderate inhibition toward hrFAAH (IC50 = 0.24 mu M). In contrast to hrFAAH, R-enantiomer 52 was more potent in inhibiting the activity of hrMAGL compared to S-enantiomer 51 (IC50 = 4.0 mu M and 16% inhibition at 10 mu M, respectively). The FAAH selectivity of the compound Si over the supposed main off-targets, MAGL and COX, was found to be >900-fold. In addition, activity-based protein profiling (ABPP) indicated high selectivity over other serine hydrolases. Finally, the selected Senantiomers 51, 53, and 55 were shown to be tight binding, slowly reversible inhibitors of the hrFAAH.

  • 10.
    Rojo, Maria Luisa
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Cipriano, Mariateresa
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Söderstrom, Ingegerd
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Simonyte, Kotryna
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Olsson, Tommy
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Fowler, Christopher J.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Effects of dietary glucose and fructose upon cannabinoid CB1 receptor functionality in the rat brain: a pilot study2014In: Life Sciences, ISSN 0024-3205, E-ISSN 1879-0631, Vol. 108, no 2, p. 116-121Article in journal (Refereed)
    Abstract [en]

    Aims: A high consumption of fructose leads not only to peripheral changes in insulin sensitivity and vascular function, but also to central changes in several brain regions. Given the role of the endogenous cannabinoid system in the control of energy intake, we undertook a pilot study to determine whether a high fructose diet produced changes in brain CB1 receptor functionality. Main methods: Male rats given access ad libitum to normal chow were given either water, glucose or fructose solutions to drink. CBI receptor functionality was measured autoradiographically as the increase in [35SJGTP)/S binding produced by the agonist CP55,940. Key findings: Seven regions were investigated: the prefrontal cortex, caudate-putamen, hippocampal CAI-CA3, dentate gyrus, amygdala, and dorsomedial and ventromedial hypothalami. Two-way robust Wilcoxon analyses for each brain region indicated that the dietary treatment did not produce significant main effects upon agonist-stimulated [35S]GThyS binding in any of the regions, in contrast to a significant main effect upon both leptin and adiponectin levels in the blood. However, a MANCOVA of the data controlling for leptin and adiponectin as co-variables identified a significant effect of glucose and fructose treatment for five weeks upon the [35S]GTPI/S response in the ventromedial hypothalamus, a region of importance for regulation of appetite. Significance: It is concluded from this pilot study that palatable solutions do not produce overt changes in brain CBI receptor functionality, although subtle changes in discrete brain regions may occur.

  • 11. Sadovski, Oleg
    et al.
    Hicks, Justin W
    Parkes, Jun
    Raymond, Roger
    Nobrega, Jose
    Houle, Sylvain
    Cipriano, Mariateresa
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Fowler, Christopher J
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Vasdev, Neil
    Wilson, Alan A
    Development and characterization of a promising fluorine-18 labelled radiopharmaceutical for in vivo imaging of fatty acid amide hydrolase2013In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 21, no 14, p. 4351-4357Article in journal (Refereed)
    Abstract [en]

    Fatty acid amide hydrolase (FAAH), the enzyme responsible for terminating signaling by the endocannabinoid anandamide, plays an important role in the endocannabinoid system, and FAAH inhibitors are attractive drugs for pain, addiction, and neurological disorders. The synthesis, radiosynthesis, and evaluation, in vitro and ex vivo in rat, of an F-18-radiotracer designed to image FAAH using positron emission tomography (PET) is described. Fluorine-18 labelled 3-(4,5-dihydrooxazol-2-yl)phenyl (5-fluoropentyl)carbamate, [F-18]5, was synthesized at high specific activity in a one-pot three step reaction using a commercial module with a radiochemical yield of 17-22% (from [F-18]fluoride). In vitro assay using rat brain homogenates showed that 5 inhibited FAAH in a time-dependent manner, with an IC50 value of 0.82 nM after a preincubation of 60 min. Ex vivo biodistribution studies and ex vivo autoradiography in rat brain demonstrated that [F-18]5 had high brain penetration with standard uptake values of up to 4.6 and had a regional distribution which correlated with reported regional FAAH enzyme activity. Specificity of binding to FAAH with [H-18]5 was high (>90%) as demonstrated by pharmacological challenges with potent and selective FAAH inhibitors and was irreversible as demonstrated by radioactivity measurements on homogenized brain tissue extracts. We infer from these results that [F-18]5 is a highly promising candidate radiotracer with which to image FAAH in human subjects using PET and clinical studies are proceeding.

    (C) 2013 The Authors. Published by Elsevier Ltd. All rights reserved.

  • 12.
    Sunduru, Naresh
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Svensson, Mona
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Cipriano, Mariateresa
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Marwaha, Sania
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Andersson, David C.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Svensson, Richard
    Fowler, Christopher J.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Elofsson, Mikael
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    N-aryl 2-aryloxyacetamides as a new class of fatty acid amide hydrolase (FAAH) inhibitors2017In: 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)
    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.

  • 13. Wheal, Amanda J.
    et al.
    Cipriano, Mariateresa
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Fowler, Christopher J.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Randall, Michael D.
    O'Sullivan, Saoirse Elizabeth
    Cannabidiol Improves Vasorelaxation in Zucker Diabetic Fatty Rats through Cyclooxygenase Activation2014In: Journal of Pharmacology and Experimental Therapeutics, ISSN 0022-3565, E-ISSN 1521-0103, Vol. 351, no 2, p. 457-466Article in journal (Refereed)
    Abstract [en]

    Cannabidiol (CBD) decreases insulitis, inflammation, neuropathic pain, and myocardial dysfunction in preclinical models of diabetes. We recently showed that CBD also improves vasorelaxation in the Zucker diabetic fatty (ZDF) rat, and the objective of the present study was to establish the mechanisms underlying this effect. Femoral arteries from ZDF rats and ZDF lean controls were isolated, mounted on a myograph, and incubated with CBD (10 mu M) or vehicle for 2 hours. Subsequent vasorelaxant responses were measured in combination with various interventions. Prostaglandin metabolites were detected using enzyme immunoassay. Direct effects of CBD on cyclooxygenase (COX) enzyme activity were measured by oxygraph assay. CBD enhanced the maximum vasorelaxation to acetylcholine (ACh) in femoral arteries from ZDF lean rats (P < 0.01) and especially ZDF rats (P < 0.0001). In ZDF arteries, this enhancement persisted after cannabinoid receptor (CB) type 1, endothelial CB, or peroxisome proliferator-activated receptor-gamma antagonism but was inhibited by CB2 receptor antagonism. CBD also uncovered a vasorelaxant response to a CB2 agonist not previously observed. The CBD-enhanced ACh response was endothelium-, nitric oxide-, and hydrogen peroxide-independent. It was, however, COX-1/2- and superoxide dismutase-dependent, and CBD enhanced the activity of both purified COX-1 and COX-2. The CBD-enhanced ACh response in the arteries was inhibited by a prostanoid EP4 receptor antagonist. Prostaglandin E-2 metabolite levels were below the limits of detection, but 6-keto prostaglandin F-1 alpha was decreased after CBD incubation. These data show that CBD exposure enhances the ability of arteries to relax via enhanced production of vasodilator COX-1/2-derived products acting at EP4 receptors.

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