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Cipriano, Mariateresa
Publications (10 of 13) Show all publications
Deplano, A., Cipriano, M., Moraca, F., Novellino, E., Catalanotti, B., Fowler, C. J. & Onnis, V. (2019). Benzylamides and piperazinoarylamides of ibuprofen as fatty acid amide hydrolase inhibitors. Journal of enzyme inhibition and medicinal chemistry (Print), 34(1), 562-576
Open this publication in new window or tab >>Benzylamides and piperazinoarylamides of ibuprofen as fatty acid amide hydrolase inhibitors
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2019 (English)In: 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) Published
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.

Place, publisher, year, edition, pages
Taylor & Francis, 2019
Keywords
Ibuprofen amides, FAAH inhibition, fatty acid amide hydrolase, endocannabinoids, induced fit docking
National Category
Pharmacology and Toxicology Medicinal Chemistry
Identifiers
urn:nbn:se:umu:diva-156327 (URN)10.1080/14756366.2018.1532418 (DOI)000456778800001 ()30688118 (PubMedID)
Available from: 2019-02-13 Created: 2019-02-13 Last updated: 2019-11-19Bibliographically 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
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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
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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
Hernández-Torres, G., Cipriano, M., Hedén, E., Björklund, E., Canales, Á., Zian, D., . . . López-Rodríguez, M. L. (2014). A reversible and selective inhibitor of monoacylglycerol lipase ameliorates multiple sclerosis. Angewandte Chemie International Edition, 53(50), 13765-13770
Open this publication in new window or tab >>A reversible and selective inhibitor of monoacylglycerol lipase ameliorates multiple sclerosis
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2014 (English)In: Angewandte Chemie International Edition, ISSN 1433-7851, E-ISSN 1521-3773, Vol. 53, no 50, p. 13765-13770Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
Wiley-VCH Verlagsgesellschaft, 2014
Keywords
endocannabinoids, endogenous cannabinoid system, enzyme inhibitors, monoacylglycerol lipase, ltiple sclerosis
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-97884 (URN)10.1002/anie.201407807 (DOI)000345833100020 ()
Available from: 2015-01-16 Created: 2015-01-08 Last updated: 2019-11-19Bibliographically approved
Wheal, A. J., Cipriano, M., Fowler, C. J., Randall, M. D. & O'Sullivan, S. E. (2014). Cannabidiol Improves Vasorelaxation in Zucker Diabetic Fatty Rats through Cyclooxygenase Activation. Journal of Pharmacology and Experimental Therapeutics, 351(2), 457-466
Open this publication in new window or tab >>Cannabidiol Improves Vasorelaxation in Zucker Diabetic Fatty Rats through Cyclooxygenase Activation
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2014 (English)In: Journal of Pharmacology and Experimental Therapeutics, ISSN 0022-3565, E-ISSN 1521-0103, Vol. 351, no 2, p. 457-466Article in journal (Refereed) Published
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.

National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:umu:diva-100158 (URN)10.1124/jpet.114.217125 (DOI)000348739800015 ()25212218 (PubMedID)
Available from: 2015-02-25 Created: 2015-02-24 Last updated: 2018-06-07Bibliographically approved
Rojo, M. L., Cipriano, M., Söderstrom, I., Simonyte, K., Olsson, T. & Fowler, C. J. (2014). Effects of dietary glucose and fructose upon cannabinoid CB1 receptor functionality in the rat brain: a pilot study. Life Sciences, 108(2), 116-121
Open this publication in new window or tab >>Effects of dietary glucose and fructose upon cannabinoid CB1 receptor functionality in the rat brain: a pilot study
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2014 (English)In: Life Sciences, ISSN 0024-3205, E-ISSN 1879-0631, Vol. 108, no 2, p. 116-121Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
Elsevier, 2014
Keywords
Fructose, Endocannabinoid, fructose, endocannabinoid, CB1 receptors, [S-35]GTP gamma S autoradiography, leptin, adiponectin
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:umu:diva-91832 (URN)10.1016/j.lfs.2014.05.019 (DOI)000339367100008 ()
Available from: 2014-09-01 Created: 2014-08-18 Last updated: 2018-06-07Bibliographically approved
Häggström, J., Cipriano, M., Plym Forshell, L., Persson, E., Hammarsten, P., Stella, N. & Fowler, C. J. (2014). Potential upstream regulators of cannabinoid receptor 1 signaling in prostate cancer: A Bayesian network analysis of data from a tissue microarray. The Prostate, 74(11), 1107-1117
Open this publication in new window or tab >>Potential upstream regulators of cannabinoid receptor 1 signaling in prostate cancer: A Bayesian network analysis of data from a tissue microarray
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2014 (English)In: The Prostate, ISSN 0270-4137, E-ISSN 1097-0045, Vol. 74, no 11, p. 1107-1117Article in journal (Refereed) Published
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.

Keywords
prostate cancer, epidermal growth factor, cannabinoid receptor, fatty acid amide hydrolase, directed acyclic graph
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-91251 (URN)10.1002/pros.22827 (DOI)000338039700004 ()
Available from: 2014-07-31 Created: 2014-07-28 Last updated: 2019-11-25Bibliographically approved
Cipriano, M., Gouveia-Figueira, S., Persson, E., Nording, M. & Fowler, C. (2014). The influence of monoacylglycerol lipase inhibition upon the expression of epidermal growth factor receptor in human PC-3 prostate cancer cells.. BMC Research Notes, 7, 441-447
Open this publication in new window or tab >>The influence of monoacylglycerol lipase inhibition upon the expression of epidermal growth factor receptor in human PC-3 prostate cancer cells.
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2014 (English)In: BMC Research Notes, ISSN 1756-0500, E-ISSN 1756-0500, Vol. 7, p. 441-447Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
BioMed Central, 2014
Keywords
Prostate cancer; Epidermal growth factor; Cannabinoid receptor; Monoacylglycerol lipase
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-101346 (URN)10.1186/1756-0500-7-441 (DOI)
Available from: 2015-03-27 Created: 2015-03-27 Last updated: 2018-06-07Bibliographically approved
Cipriano, M., Häggström, J., Hammarsten, P. & Fowler, C. J. (2013). Association between cannabinoid CB1 receptor expression and Akt signalling in prostate cancer. PLoS ONE, 8(6), e65798
Open this publication in new window or tab >>Association between cannabinoid CB1 receptor expression and Akt signalling in prostate cancer
2013 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 6, p. e65798-Article in journal (Refereed) Published
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.

National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:umu:diva-79271 (URN)10.1371/journal.pone.0065798 (DOI)000320579400077 ()
Available from: 2013-09-04 Created: 2013-08-13 Last updated: 2018-06-08Bibliographically approved
Patel, J. Z., Parkkari, T., Laitinen, T., Kaczor, A. A., Saario, S. M., Savinainen, J. R., . . . Nevalainen, T. (2013). Chiral 1,3,4-Oxadiazol-2-ones as Highly Selective FAAH Inhibitors. Journal of Medicinal Chemistry, 56(21), 8484-8496
Open this publication in new window or tab >>Chiral 1,3,4-Oxadiazol-2-ones as Highly Selective FAAH Inhibitors
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2013 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 56, no 21, p. 8484-8496Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2013
National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:umu:diva-84115 (URN)10.1021/jm400923s (DOI)000327111100021 ()
Available from: 2013-12-18 Created: 2013-12-16 Last updated: 2018-06-08Bibliographically approved
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