Consorzio ELPRO

Pula CA, Italy

Consorzio ELPRO

Pula CA, Italy

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Manca I.,Neuroscienze PharmaNess S.c.a R.l. | Mastinu A.,Instituto Of Farmacologia Traslazionale | Olimpieri F.,Polytechnic of Milan | Falzoi M.,Consorzio ELPRO | And 15 more authors.
European Journal of Medicinal Chemistry | Year: 2013

In spite of rimonabant's withdrawal from the European market due to its adverse effects, interest in the development of drugs based on CB1 antagonists is revamping on the basis of the peculiar properties of this class of compounds. In particular, new strategies have been proposed for the treatment of obesity and/or related risk factors through CB1 antagonists, i.e. by the development of selectively peripherally acting agents or by the identification of neutral CB1 antagonists. New compounds based on the lead CB1 antagonist/inverse agonist rimonabant have been synthesized with focus on obtaining neutral CB1 antagonists. Amongst the new derivatives described in this paper, the mixture of the two enantiomers (±)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-3-(2-cyclohexyl-1- hydroxyethyl)-4-methyl-1H-pyrazole ((±)-5), and compound 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-3-[(Z)-2-cyclohexyl-1-fluorovinyl] -4-methyl-1H-pyrazole ((Z)-6), showed interesting pharmacological profiles. According to the preliminary pharmacological evaluation, these novel pyrazole derivatives showed in fact both neutral CB1 antagonism behaviour and significant in vivo activity towards food intake. © 2012 Elsevier Masson SAS. All rights reserved.

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.

Loriga G.,National Research Council Italy | Lazzari P.,Neuroscienze PharmaNess S.c.a r.l. | Lazzari P.,KemoTech S.r.l. | Lazzari P.,University of Sassari | And 8 more authors.
Bioorganic and Medicinal Chemistry | Year: 2015

Here we report the investigation of diazabicycloalkane cores as potential new scaffolds for the development of novel analogues of the previously reported diazatricyclodecane selective delta (δ) opioid agonists, as conformationally constrained homologues of the reference δ agonist (+)-4-[(α. R)-α((2. S,5. R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,. N-diethylbenzamide (SNC80).In particular, we have simplified the diazatricyclodecane motif of δ opioid agonist prototype 1a with bridged bicyclic cores. 3,6-diazabicyclo[3.1.1]heptane, 3,8-diazabicyclo[3.2.1]octane, 3,9-diazabicyclo[3.3.1]nonane, 3,9-diazabicyclo[4.2.1]nonane, and 3,10-diazabicyclo[4.3.1]decane were adopted as core motifs of the novel derivatives. The compounds were synthesized and biologically assayed as racemic (3-5) or diastereoisomeric (6,. 7) mixtures.All the novel compounds 3-7 showed δ agonism behaviour and remarkable affinity to δ receptors. Amongst the novel derivatives, 3,8-diazabicyclo[3.2.1]octane based compound 4 evidenced improved δ affinity and selectivity relative to SNC80. © 2015.

Pinna G.,University of Sassari | Loriga G.,National Research Council Italy | Lazzari P.,University of Sassari | Lazzari P.,KemoTech Srl | And 8 more authors.
European Journal of Medicinal Chemistry | Year: 2014

A new series of 1H-benzofuro[3,2-c]pyrazole-3-carboxamides was synthesized. The novel compounds (15-24) were evaluated for their affinity to CB2 and CB1 cannabinoid receptors. The synthesis of the title compounds takes advantage of the acid-catalysed thermal cyclization of bicyclic hydrazone ethyl 2-(2-(2,4-dichlorophenyl)hydrazono)-2-(6-methyl-3-oxo-2,3- dihydrobenzofuran-2-yl)acetate to tricyclic ethyl 1-(2,4-dichlorophenyl)-6- methyl-1H-benzofuro[3,2-c]pyrazol-3-carboxylate. All the obtained derivatives showed high affinity to CB2 receptors. Moreover, significant selectivity for CB2 over CB1 receptors was highlighted for lead derivatives amongst the novel series. The best binding profiles were determined for homologues bearing monocyclic and bicyclic monoterpenic substituents at the carbamoyl group at 3 position of the pyrazole ring (K iCB2 < 4 nM). In particular, the isopinocampheyl- substituted derivative 22 exhibited the highest selectivity for CB2 receptors with Ki values of 3.7 and 2398 nM for CB2 and CB1 receptors, respectively. Preliminary functional assays evidenced CB2 agonism behaviour for all the assayed novel derivatives. © 2014 Elsevier Masson SAS. All rights reserved.

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