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Lazzari P.,Neuroscienze PharmaNess S.c.ar.l. | Lazzari P.,CNR Institute of Biomedical Technologies | Sanna A.,Neuroscienze PharmaNess S.c.ar.l. | Mastinu A.,Neuroscienze PharmaNess S.c.ar.l. | And 6 more authors.
Behavioural Brain Research | Year: 2011

This study investigates the molecular mechanisms and the center-periphery cross talk underlying the anti-obesity effect of the cannabinoid receptor 1 (CB1) antagonist/inverse agonist rimonabant in diet-induced obese (DIO) mice exposed to a 31 days chronic treatment with the drug. Present data showed a significant and stable weight loss both in animals treated with rimonabant 10mg/kg by oral gavage exposed to a high fat diet (SRFD) and in vehicle treated mice switched to a regular chow (VEND) with respect to vehicle fat diet fed mice (VEFD). Caloric intake was significantly lowered in SRFD and VEND during the first two and four days, respectively, then reaching the VEFD consume throughout the treatment. The drop of body weight was accompanied by leptin mRNA decrease in visceral fat tissue both in VEND and SRFD, as revealed by Real time PCR analysis. No difference in CB1 mRNA receptor expression in hypothalamus and in visceral fat tissue among groups was observed. Leptin receptors were decreased in the hypothalamus of SRFD but not of VEND mice. Moreover, in SRFD and VEND mice the expression of orexigenic genes Neuropeptide Y and Agouti Related Protein (AGRP) was increased, while anorexigenic ones, Pro-OpioMelanoCortin (POMC) and Cocaine-and-Amphetamine-Regulated Transcript (CART) displayed no alteration in any group. This data contribute to clarify the molecular basis of the anti-obesity properties of rimonabant, underlying the role of the peripheral modulators which affect central circuits involved in the regulation of food intake and energy homeostasis. © 2010 Elsevier B.V.


Tambaro S.,Neuroscienze PharmaNess S.c.a.r.l. | Reali R.,Neuroscienze PharmaNess S.c.a.r.l. | Volonterio A.,Polytechnic of Milan | Volonterio A.,CNR Institute of Chemistry of Molecular Recognition | And 7 more authors.
Pharmacology Biochemistry and Behavior | Year: 2013

For the past few decades membrane zinc metallopeptidases have been identified as important therapeutic targets in the control of pain. In particular, neutral endopeptidase (NEP) has been shown to play critical roles in the metabolism of the endogenous peptides Met- and Leu-enkephalins. In this study, we have evaluated the activity of a new fluorinated peptidase inhibitor NESS002ie in both in vitro and in vivo assays. NESS002ie has been compared to the peptidomimetic compound thiorphan and the previously reported NEP selective thiol inhibitor C20. The metallopeptidases inhibitory activity of NESS002ie was tested in vitro using a highly, sensitive, continuous, fluorometric, enzyme assay. Also, the analgesic propriety of NESS002ie, thiorphan and C20 have been evaluated in vivo, by intraplantar, intravenous and intrathecal administration, through nociception assays based on formalin test in mice. Metallopeptidases assays have shown an inhibitory potency of NESS002ie in the nanomolar range for NEP and angiotensin-converting enzyme (ACE). The new fluorinated inhibitor showed higher analgesic activity and bioavailability compared to thiorphan and C20 when administered by both intravenous and intrathecal injections. More significantly, intrathecal injection of NESS002ie reduced both the first and the second phases of the formalin biphasic pain response. In addition, naltrindole and naloxone reversed the analgesic effect of NESS002ie with a diverse profile. This study shows an improvement in relief of inflammation and pain, in vivo, using NESS002ie compared to reference compounds thiorphan and C20. This significant effect could be due to the replacement of isobutyl chain of the thiol C20 with the trifluoromethyl group. © 2013 Elsevier Inc. All rights reserved.


Frau S.,University of Aberdeen | Dall'Angelo S.,University of Aberdeen | Baillie G.L.,University of Aberdeen | Ross R.A.,University of Aberdeen | And 6 more authors.
Journal of Fluorine Chemistry | Year: 2013

A novel class of cannabinoid ligands was synthesized in good overall yields by means of oxime-bio-conjugation between hydroxylamine-functionalized Rimonabant-type pyrazoles and fluoro-deoxy-carbohydrates (D-2-fluoro-deoxy- glucose, FDG, and D-5-fluoro-5-deoxy-ribose, FDR). FDR proved to be superior to FDG for bio-conjugation, as it occurred in milder conditions and at faster rate (rt, 20 min vs. 100 8C, 30 min). All of the title compounds showed relatively modest affinity for the CB1 receptor (high nanomolar range) and selectivities vs. the CB2. © 2013 Elsevier B.V. All rights reserved.


Distinto R.,University of Pula | Zanato C.,University of Aberdeen | Montanari S.,University of Aberdeen | Cascio M.G.,University of Aberdeen | And 4 more authors.
Journal of Fluorine Chemistry | Year: 2014

Replacement of the 3-carbonylaminopiperidine substitutent with a "click" 4-[N-(4-fluorobutyl)-(1,2,3-triazolyl)] group in Rimonabant-type pyrazoles produced a novel class of nanomolar CB1 receptor ligands. Molecule 1d is the most promising lead with a K i =23nM for CB1, which is very close to that displayed by Rimonabant (SR141716), and fairly good CB1/CB2 selectivity (K i CB2/K i CB1 =35.5), thus representing a promising candidate for [18F]radiolabeling and PET Imaging studies of the CB1 receptor. © 2014 Elsevier B.V.


Grant
Agency: Cordis | Branch: FP7 | Program: MC-IAPP | Phase: FP7-PEOPLE-2009-IAPP | Award Amount: 930.58K | Year: 2010

The development of innovative technology for the introduction of PET-radionuclides (18F, 11C, etc.) in organic compounds, as well as the identification of new radiolabeled molecules suitable for being used as PET tracers is one of the priorities in the areas of Applied Chemistry and Medical Technologies. First objective of this project is the identification of novel radiolabeled CB1 (cannabinoid) receptor ligands with an emphasis on the development of innovative synthetic methodologies for the introduction of 18F and 11C radioisotopes. These CB1 radioligands could be used at least in a couple of different ways. First to see whether the potential CB1 ligand makes it to the brain, where CB1 receptors are predominantly located, and what other organs sequester the drug. Second, to see how good is the affinity of the CB1 radioligands, an information that can be critical in dosimetry studies. The most promising and effective CB1 radioligands will be further investigated with the view of introducing chemical functions suitable for the development of multi-modal contrast agents for PET-CT, MRI, fluorescence and ultrasound. As an example, the radioligands will be functionalized with fluorescent tags, or chelating functions for paramagnetic metal cations for MRI use. The main goals of the project are (1) the identification of novel CB1 receptor radioligands with potential for clinical development, (2) a detailed study of their use for brain imaging, with the objective to use these PET-tracer molecules to visualize CB1-receptor related processes in the brain of animal models, with the future perspective of using these novel molecular tools as diagnostic tools in human brains. The partners in this project are (1) the University of Aberdeen (Scotland, UK), which is strong in the area of radiochemistry and imaging, and (2) Pharmaness-Neuroscienze (Sardinia, Italy) a research-driven SME with strong expertise in the area of cannabinoids.


Murgia S.,University of Cagliari | Fadda P.,Consorzio ELPRO | Colafemmina G.,University of Bari | Angelico R.,University of Molise | And 5 more authors.
Journal of Colloid and Interface Science | Year: 2013

Here, the phase behavior of the commercial non-ionic surfactant Solutol® HS15 in water was investigated. The focus was on the evolution of the system nanostructure at low water content. Particularly, it was demonstrated that spherical micelles found in dilute surfactant solutions coalesce at a surfactant volume fraction close to 0.5. As consequence, a heterogeneous pseudo-binary mixture occurs. No liquid crystalline phases were detected even at the highest HS15 concentrations in water. Alteration of the micellar morphology induced by the addition of Δ9-tetrahydrocannabinol to the surfactant/water binary system was also investigated. It was found that the cannabinoid molecules become entrapped within the surfactant hydrophobic tails, thus increasing the surfactant effective packing parameter and inducing a radical change of the micelle shape. At sufficiently low water content (18-35wt.%), such alteration of the interfacial packing results in a lamellar organization of the surfactant molecules. © 2012 Elsevier Inc.


Patent
Neuroscienze Pharmaness S.C.A.R.L. | Date: 2010-02-25

Condensed tricyclic pyrazole compounds having affinity for the CB1 and/or CB2 cannabinoidergic receptors, with activity both on the peripheral and central nervous system, of formula (I): wherein:


PubMed | Neuroscienze PharmaNess S.c.a.r.l.
Type: | Journal: Pharmacology, biochemistry, and behavior | Year: 2013

For the past few decades membrane zinc metallopeptidases have been identified as important therapeutic targets in the control of pain. In particular, neutral endopeptidase (NEP) has been shown to play critical roles in the metabolism of the endogenous peptides Met- and Leu-enkephalins. In this study, we have evaluated the activity of a new fluorinated peptidase inhibitor NESS002ie in both in vitro and in vivo assays. NESS002ie has been compared to the peptidomimetic compound thiorphan and the previously reported NEP selective thiol inhibitor C20. The metallopeptidases inhibitory activity of NESS002ie was tested in vitro using a highly, sensitive, continuous, fluorometric, enzyme assay. Also, the analgesic propriety of NESS002ie, thiorphan and C20 have been evaluated in vivo, by intraplantar, intravenous and intrathecal administration, through nociception assays based on formalin test in mice. Metallopeptidases assays have shown an inhibitory potency of NESS002ie in the nanomolar range for NEP and angiotensin-converting enzyme (ACE). The new fluorinated inhibitor showed higher analgesic activity and bioavailability compared to thiorphan and C20 when administered by both intravenous and intrathecal injections. More significantly, intrathecal injection of NESS002ie reduced both the first and the second phases of the formalin biphasic pain response. In addition, naltrindole and naloxone reversed the analgesic effect of NESS002ie with a diverse profile. This study shows an improvement in relief of inflammation and pain, in vivo, using NESS002ie compared to reference compounds thiorphan and C20. This significant effect could be due to the replacement of isobutyl chain of the thiol C20 with the trifluoromethyl group.


Peddio G.,Consorzio El Pro | Peddio G.,National Research Council Italy | Pittau B.,National Research Council Italy | Manca I.,National Research Council Italy | And 3 more authors.
Chromatographia | Year: 2014

A sensitive and selective LC-MS/MS method for the quantification of the atypical antipsychotic agent quetiapine and its metabolite norquetiapine (N-desalkyl quetiapine) was developed and validated. Following the protein precipitation technique, the analytes were separated using a reversed phase column with gradient elution. The compounds were ionized in the electrospray positive ionization (ESI+) ion source tandem MS detection in multiple reaction monitoring (MRM) mode. Calibration curves were generated by plotting the peak area ratio of quetiapine and norquetiapine to the IS clozapine for each calibration concentration. The method provides a linear response from a quantitation range of 2.3-452.9 nM (0.9-173.7 ng/mL) and 2.7-543.0 nM (1.0-200.0 ng/mL) for quetiapine and norquetiapine, respectively. Regression analysis showed a correlation coefficient greater than 0.999 and 0.991 for quetiapine and norquetiapine, respectively. To evaluate the metabolism of quetiapine by the cytochrome P450 in microsomes, the method has been subsequently employed. LC-MS/MS procedure has been carried out to determine increasing concentrations of both drugs in microsomal matrix obtained by a pool of mammalian liver microsomes BD UltraPoolTM Human Liver Microsomes (HLM 150). © 2013 Springer-Verlag Berlin Heidelberg.


PubMed | Neuroscienze PharmaNess S.c.ar.l.
Type: Journal Article | Journal: Behavioural brain research | Year: 2010

This study investigates the molecular mechanisms and the center-periphery cross talk underlying the anti-obesity effect of the cannabinoid receptor 1 (CB(1)) antagonist/inverse agonist rimonabant in diet-induced obese (DIO) mice exposed to a 31 days chronic treatment with the drug. Present data showed a significant and stable weight loss both in animals treated with rimonabant 10mg/kg by oral gavage exposed to a high fat diet (SRFD) and in vehicle treated mice switched to a regular chow (VEND) with respect to vehicle fat diet fed mice (VEFD). Caloric intake was significantly lowered in SRFD and VEND during the first two and four days, respectively, then reaching the VEFD consume throughout the treatment. The drop of body weight was accompanied by leptin mRNA decrease in visceral fat tissue both in VEND and SRFD, as revealed by Real time PCR analysis. No difference in CB(1) mRNA receptor expression in hypothalamus and in visceral fat tissue among groups was observed. Leptin receptors were decreased in the hypothalamus of SRFD but not of VEND mice. Moreover, in SRFD and VEND mice the expression of orexigenic genes Neuropeptide Y and Agouti Related Protein (AGRP) was increased, while anorexigenic ones, Pro-OpioMelanoCortin (POMC) and Cocaine-and-Amphetamine-Regulated Transcript (CART) displayed no alteration in any group. This data contribute to clarify the molecular basis of the anti-obesity properties of rimonabant, underlying the role of the peripheral modulators which affect central circuits involved in the regulation of food intake and energy homeostasis.

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