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Villa San Pietro, Italy

Tambaro S.,Neuroscienze PharmaNess Scarl | Reali R.,Neuroscienze PharmaNess Scarl | 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. Source


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.


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. Source


Distinto R.,University of Aberdeen | 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 Ki = 23 nM for CB1, which is very close to that displayed by Rimonabant (SR141716), and fairly good CB1/CB2 selectivity (Ki CB2/Ki CB1 = 35.5), thus representing a promising candidate for [18F]radiolabeling and PET Imaging studies of the CB1 receptor. © 2014 Elsevier B.V. All rights reserved. Source


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:

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