185 results on '"Claudio, Trapella"'
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2. Enzymatic Desymmetrisation of Prochiral meso-1,2-Disubstituted-1,2-Diaminoethane for the Synthesis of Key Enantioenriched (−)-Nutlin-3 Precursor
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Virginia Cristofori, Davide Illuminati, Chiara Bisquoli, Martina Catani, Greta Compagnin, Giulia Turrin, Claudio Trapella, and Anna Fantinati
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biocatalysis ,Nutlin-3a ,desymmetrisation ,vicinal meso-diamines ,Organic chemistry ,QD241-441 - Abstract
Herein we present the biocatalysed preparation of a mono-N-carbamate-protected precursor of antitumoral Nutlin-3a through enantioselective alkoxycarbonylation of meso-1,2-disubstituted-1,2-diaminoethane using enzyme lipases and dialkyl carbonates as acylating agents. A series of supported or free lipase enzymes were screened in combination with commercially available diallyl, diethyl and dimethyl carbonates. The reactions were conducted at different temperatures, for different reaction times and with variable co-solvent systems to evaluate the effects on the enzyme catalytic activity. The best results in terms of conversion, enantiomeric excess and yield were obtained when lipase from Candida antarctica B (CAL-B) was used with diallyl carbonate (DAC) when conducting the reaction solventless at 75 °C.
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- 2024
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3. (L)-Monomethyl Tyrosine (Mmt): New Synthetic Strategy via Bulky ‘Forced-Traceless’ Regioselective Pd-Catalyzed C(sp2)–H Activation
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Davide Illuminati, Claudio Trapella, Vinicio Zanirato, Remo Guerrini, Valentina Albanese, Chiara Sturaro, Simona Stragapede, Davide Malfacini, Greta Compagnin, Martina Catani, and Anna Fantinati
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monomethyltyrosine ,dimethyltyrosine ,catalysis ,peptides ,Medicine ,Pharmacy and materia medica ,RS1-441 - Abstract
The enormous influence in terms of bioactivity, affinity, and selectivity represented by the replacement of (L)-2,6-dimethyl tyrosine (Dmt) instead of Phenylalanine (Phe) into Nociceptin/orphanin (N/OFQ) neuropeptide analogues has been well documented in the literature. More recently, the non-natural amino acid (L)-2-methyl tyrosine (Mmt), with steric hindrance included between Tyr and Dmt, has been studied because of the modulation of steric effects in opioid peptide chains. Here, we report a new synthetic strategy to obtain Mmt based on the well-known Pd-catalyzed ortho-C(sp2)–H activation approach, because there is a paucity of other synthetic routes in the literature to achieve it. The aim of this work was to force only the mono-ortho-methylation process over the double ortho-methylation one. In this regard, we are pleased to report that the introduction of the dibenzylamine moiety on a Tyr aromatic nucleus is a convenient and traceless solution to achieve such a goal. Interestingly, our method provided the aimed Mmt either as N-Boc or N-Fmoc derivatives ready to be inserted into peptide chains through solid-phase peptide synthesis (SPPS). Importantly, the introduction of Mmt in place of Phe1 in the sequence of N/OFQ(1-13)-NH2 was very well tolerated in terms of pharmacological profile and bioactivity.
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- 2023
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4. Evaluation of the microbiological and chemical aspects of autochthonous wild snails in Sardinia
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Valentina Coroneo, Luisa Marras, Valerio Giaccone, Daniele Conficoni, Silvana Anna Stefania Brignardello, Elisa Bissacco, Claudio Trapella, Andrea Alogna, Valentina Gentili, Antonio Parisi, Federica Loi, Stefano Cappai, Margherita Pisanu, and Maria Paola Cogoni
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Snails ,Listeria monocytogenes ,Salmonella spp ,Heavy metals ,Food safety ,Food processing and manufacture ,TP368-456 - Abstract
This study was conducted to acquire knowledge on the epidemiology and ecology of some zoonotic agents in snails. Chemical and microbiological analysis was carried out on 46 samples of snails belonging to the species of Helix aspersa and Helix (Eobania) vermiculata. The association between heavy metals and wild snails, a native consumer product in the Region of Sardinia, was determined. The molecular characterisation of Listeria monocytogenes virulence genes has shown a genetic profile that deserves more attention for the improvement of surveillance and risk prevention. Specimens of H. vermiculata showed higher concentrations of cadmium (M=0.80±0.56 mg/kg) than H. aspersa (M=0.61±0.17 mg /kg). A further objective was to determine whether the samples showed significant differences from the point of view of secretion characterisation, in terms of protein content, and to identify species-specific correlations and possible relationships with the environment. The presence of Salmonella enterica sub.sp houtenae (6,14: z4, z23) and Salmonella enterica subsp diarizonae (47: k: e, n, z15) (1 sample), Listeria monoSnails,cytogenes (2 samples) with Molecular characterization of virulence genes together with the measurement of heavy metals in samples of wild snails has shown a health and hygiene profile that would deserve greater attention for the improvement of the surveillance and prevention of microbiological and chemical risk in such products which currently show a tendency towards increase in consumption.
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- 2022
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5. 1,3,8-Triazaspiro[4.5]decane Derivatives Inhibit Permeability Transition Pores through a FO-ATP Synthase c Subunit Glu119-Independent Mechanism That Prevents Oligomycin A-Related Side Effects
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Gaia Pedriali, Daniela Ramaccini, Esmaa Bouhamida, Alessio Branchini, Giulia Turrin, Elisabetta Tonet, Antonella Scala, Simone Patergnani, Mirko Pinotti, Claudio Trapella, Carlotta Giorgi, Elena Tremoli, Gianluca Campo, Giampaolo Morciano, and Paolo Pinton
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permeability transition pore ,Oligomycin A ,c subunit of FO-ATP synthase ,small molecules ,cardioprotection ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Permeability transition pore (PTP) molecular composition and activity modulation have been a matter of research for several years, especially due to their importance in ischemia reperfusion injury (IRI). Notably, c subunit of ATP synthase (Csub) has been identified as one of the PTP-forming proteins and as a target for cardioprotection. Oligomycin A is a well-known Csub interactor that has been chemically modified in-depth for proposed new pharmacological approaches against cardiac reperfusion injury. Indeed, by taking advantage of its scaffold and through focused chemical improvements, innovative Csub-dependent PTP inhibitors (1,3,8-Triazaspiro[4.5]decane) have been synthetized in the past. Interestingly, four critical amino acids have been found to be involved in Oligomycin A-Csub binding in yeast. However, their position on the human sequence is unknown, as is their function in PTP inhibition. The aims of this study are to (i) identify for the first time the topologically equivalent residues in the human Csub sequence; (ii) provide their in vitro validation in Oligomycin A-mediated PTP inhibition and (iii) understand their relevance in the binding of 1,3,8-Triazaspiro[4.5]decane small molecules, as Oligomycin A derivatives, in order to provide insights into Csub interactions. Notably, in this study we demonstrated that 1,3,8-Triazaspiro[4.5]decane derivatives inhibit permeability transition pores through a FO-ATP synthase c subunit Glu119-independent mechanism that prevents Oligomycin A-related side effects.
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- 2023
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6. The Fascinating Chemistry of α‐Haloamides
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Dr. Anna Fantinati, Prof. Vinicio Zanirato, Dr. Paolo Marchetti, and Prof. Claudio Trapella
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amides ,electrochemistry ,photocatalysis ,radical reactions ,reaction mechanisms ,Chemistry ,QD1-999 - Abstract
Abstract The aim of this review is to highlight the rich chemistry of α‐haloamides originally mainly used to discover new C−N, C−O and C−S bond forming reactions, and later widely employed in C−C cross‐coupling reactions with C(sp3), C(sp2) and C(sp) coupling partners. Radical‐mediated transformations of α‐haloamides bearing a suitable located unsaturated bond has proven to be a straightforward alternative to access diverse cyclic compounds by means of either radical initiators, transition metal redox catalysis or visible light photoredox catalysis. On the other hand, cycloadditions with α‐halohydroxamate‐based azaoxyallyl cations have garnered significant attention. Moreover, in view of the important role in life and materials science of difluoroalkylated compounds, a wide range of catalysts has been developed for the efficient incorporation of difluoroacetamido moieties into activated as well as unactivated substrates.
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- 2020
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7. The Evolution of Ketosis: Potential Impact on Clinical Conditions
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Latha Nagamani Dilliraj, Giovanna Schiuma, Djidjell Lara, Giovanni Strazzabosco, James Clement, PierPaolo Giovannini, Claudio Trapella, Marco Narducci, and Roberta Rizzo
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beta-hydroxybutyrate ,evolution ,ketogenesis ,anti-inflammatory ,Nutrition. Foods and food supply ,TX341-641 - Abstract
Ketone bodies are small compounds derived from fatty acids that behave as an alternative mitochondrial energy source when insulin levels are low, such as during fasting or strenuous exercise. In addition to the metabolic function of ketone bodies, they also have several signaling functions separate from energy production. In this perspective, we review the main current data referring to ketone bodies in correlation with nutrition and metabolic pathways as well as to the signaling functions and the potential impact on clinical conditions. Data were selected following eligibility criteria accordingly to the reviewed topic. We used a set of electronic databases (Medline/PubMed, Scopus, Web of Sciences (WOS), Cochrane Library) for a systematic search until July 2022 using MeSH keywords/terms (i.e., ketone bodies, BHB, acetoacetate, inflammation, antioxidant, etc.). The literature data reported in this review need confirmation with consistent clinical trials that might validate the results obtained in in vitro and in vivo in animal models. However, the data on exogenous ketone consumption and the effect on the ketone bodies’ brain uptake and metabolism might spur the research to define the acute and chronic effects of ketone bodies in humans and pursue the possible implication in the prevention and treatment of human diseases. Therefore, additional studies are required to examine the potential systemic and metabolic consequences of ketone bodies.
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- 2022
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8. A Cationic Contrast Agent in X-ray Imaging of Articular Cartilage: Pre-Clinical Evaluation of Diffusion and Attenuation Properties
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Simone Fantoni, Ilenia Gabucci, Paolo Cardarelli, Gianfranco Paternò, Angelo Taibi, Virginia Cristofori, Claudio Trapella, Armando Bazzani, Marta Assenza, Alice Zanna Bonacorsi, Daniele Conti, and Fabio Baruffaldi
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X-ray imaging ,articular cartilage ,contrast agent ,contrast-enhanced computed tomography ,proteoglycans ,post-traumatic osteoarthritis ,Medicine (General) ,R5-920 - Abstract
The aim of this study was the preliminary assessment of a new cationic contrast agent, the CA4+, via the analysis of spatial distribution in cartilage of ex vivo bovine samples, at micrometer and millimeter scale. Osteochondral plugs (n = 18) extracted from bovine stifle joints (n = 2) were immersed in CA4+ solution up to 26 h. Planar images were acquired at different time points, using a microCT apparatus. The CA4+ distribution in cartilage and saturation time were evaluated. Tibial plates from bovine stifle joints (n = 3) were imaged with CT, before and after 24 h-CA4+ bath immersion, at different concentrations. Afterward, potential CA4+ washout from cartilage was investigated. From microCT acquisitions, the CA4+ distribution differentiated into three distinct layers inside the cartilage, reflecting the spatial distribution of proteoglycans. After 24 h of diffusion, the iodine concentration reached in cartilage was approximately seven times that of the CA4+ bath. The resulting saturation time was 1.9 ± 0.9 h and 2.6 ± 2.9 h for femoral and tibial samples, respectively. Analysis of clinical CT acquisitions confirmed overall contrast enhancement of cartilage after 24 h immersion, observed for each CA4+ concentration. Distinct contrast enhancement was reached in different cartilage regions, depending on tissue’s local features. Incomplete but remarkable washout of cartilage was observed. CA4+ significantly improved cartilage visualization and its qualitative analysis.
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- 2022
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9. Synthesis and NLRP3-Inflammasome Inhibitory Activity of the Naturally Occurring Velutone F and of Its Non-Natural Regioisomeric Chalconoids
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Tiziano De Ventura, Mariasole Perrone, Sonia Missiroli, Paolo Pinton, Paolo Marchetti, Giovanni Strazzabosco, Giulia Turrin, Davide Illuminati, Virginia Cristofori, Anna Fantinati, Martina Fabbri, Carlotta Giorgi, Claudio Trapella, and Vinicio Zanirato
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flavonoid ,chalcone-based compounds ,NLRP3-inflammasome inhibitors ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Plant-derived remedies rich in chalcone-based compounds have been known for centuries in the treatment of specific diseases, and nowadays, the fascinating chalcone framework is considered a useful and, above all, abundant natural chemotype. Velutone F, a new chalconoid from Millettia velutina, exhibits a potent effect as an NLRP3-inflammasome inhibitor; the search for new natural/non-natural lead compounds as NLRP3 inhibitors is a current topical subject in medicinal chemistry. The details of our work toward the synthesis of velutone F and the unknown non-natural regioisomers are herein reported. We used different synthetic strategies both for the construction of the distinctive benzofuran nucleus (BF) and for the key phenylpropenone system (PhP). Importantly, we have disclosed a facile entry to the velutone F via synthetic routes that can also be useful for preparing non-natural analogs, a prerequisite for extensive SAR studies on the new flavonoid class of NLRP3-inhibitors.
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- 2022
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10. Xylitol as a Hydrophilization Moiety for a Biocatalytically Synthesized Ibuprofen Prodrug
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Federico Zappaterra, Chiara Tupini, Daniela Summa, Virginia Cristofori, Stefania Costa, Claudio Trapella, Ilaria Lampronti, and Elena Tamburini
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ibuprofen ,xylitol ,CALB ,prodrug ,esterification ,cystic fibrosis (CF) ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Biocatalyzed synthesis can be exploited to produce high-value products, such as prodrugs. The replacement of chemical approaches with biocatalytic processes is advantageous in terms of environmental prevention, embracing the principles of green chemistry. In this work, we propose the covalent attachment of xylitol to ibuprofen to produce an IBU-xylitol ester prodrug. Xylitol was chosen as a hydrophilizer for the final prodrug, enhancing the water solubility of ibuprofen. Ibuprofen is a nonsteroidal anti-inflammatory drug (NSAID) extensively used as an analgesic, anti-inflammatory, and antipyretic. Despite being the third-most-prescribed medicine in the world, the aqueous solubility of ibuprofen is just 21 mg/L. This poor water solubility greatly limits the bioavailability of ibuprofen. We aimed to functionalize ibuprofen with xylitol using the reusable immobilized N435 biocatalyst. Instead of a biphasic media, we proposed a monophasic reaction environment. The characterization of the IBU-xylitol ester was performed by 1H, 13C-NMR, DEPT, COSY, HMQC, HMBC, FTIR, and MS spectroscopy. Preliminary in vitro tests showed that this enzymatically synthesized prodrug of ibuprofen reduced the expression of the interleukin 8 genes in human bronchial epithelial cells (IB3-1) from cystic fibrosis (CF) patients.
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- 2022
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11. HelixComplex snail mucus as a potential technology against O3 induced skin damage.
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Valentina Gentili, Daria Bortolotti, Mascia Benedusi, Andrea Alogna, Anna Fantinati, Anna Guiotto, Giulia Turrin, Carlo Cervellati, Claudio Trapella, Roberta Rizzo, and Giuseppe Valacchi
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Medicine ,Science - Abstract
Mucus form H. aspersa muller has been reported to have several therapeutic proprieties, such as antimicrobial activity, skin protection and wound repair. In this study, we have analyzed H. aspersa mucus (Helixcomplex) bio-adhesive efficacy and its defensive properties against the ozone (O3) (0.5 ppm for 2 hours) exposure in human keratinocytes and reconstructed human epidermis models. Cytotoxicity, tissue morphology and cytokine levels were determined. We confirmed HelixComplex regenerative and bio-adhesive properties, the latter possibly via the characteristic mucopolysaccharide composition. In addition, HelixComplex was able to protect from O3 exposure by preventing oxidative damage and the consequent pro-inflammatory response in both 2D and 3D models. Based on this study, it is possible to suggest HelixComplex as a potentially new protective technology against pollution induced skin damage.
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- 2020
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12. Sometimes, the Least Demanding Solution Is the Most Suitable: A Careful Survey of NMR Spectra of a Phosphonium Salt Accounted for Its 'Unusual Wittig Reaction'
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Anna Fantinati, Paolo Marchetti, Claudio Trapella, and Vinicio Zanirato
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Chemistry ,QD1-999 - Published
- 2018
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13. GlicoPro, Novel Standardized and Sterile Snail Mucus Extract for Multi-Modulative Ocular Formulations: New Perspective in Dry Eye Disease Management
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Rita Mencucci, Giovanni Strazzabosco, Virginia Cristofori, Andrea Alogna, Daria Bortolotti, Roberta Gafà, Michela Cennamo, Eleonora Favuzza, Claudio Trapella, Valentina Gentili, and Roberta Rizzo
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dry eye disease ,snail mucus ,opiorphin ,artificial tears ,corneal epithelium ,Pharmacy and materia medica ,RS1-441 - Abstract
This study aimed to evaluate the mucoadhesive and regenerative properties of a novel lubricating multimolecular ophthalmic solution (GlicoPro®) extracted from snail mucus and its potential anti-inflammatory and analgesic role in the management of dry eye disease (DED). GlicoPro bio-adhesive efficacy was assessed using a lectin-based assay, and its regenerative properties were studied in a human corneal epithelial cell line. In vitro DED was induced in human corneal tissues; the histology and mRNA expression of selected genes of inflammatory and corneal damage biomarkers were analyzed in DED tissues treated with GlicoPro. A higher percentage of bio-adhesivity was observed in corneal cells treated with GlicoPro than with sodium hyaluronate-based compounds. In the scratch test GlicoPro improved in vitro corneal wound healing. Histo-morphological analysis revealed restoration of cellular organization of the corneal epithelium, microvilli, and mucin network in DED corneal tissues treated with GlicoPro. A significant reduction in inflammatory and ocular damage biomarkers was observed. High-performance liquid chromatography-mass spectrometry analysis identified an endogenous opioid, opiorphin, in the peptide fraction of GlicoPro. In conclusion, GlicoPro induced regeneration and bio-adhesivity in corneal cells; moreover, considering its anti-inflammatory and analgesic properties, this novel ophthalmic lubricating solution may be an innovative approach for the management of DED.
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- 2021
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14. Chemoenzymatic Stereodivergent Synthesis of All the Possible Stereoisomers of the 2,3-Dimethylglyceric Acid Ethyl Ester
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Francesco Presini, Graziano Di Carmine, Pier Paolo Giovannini, Virginia Cristofori, Lindomar Alberto Lerin, Olga Bortolini, Claudio Trapella, and Anna Fantinati
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biocatalysis ,stereodivergent synthesis ,asymmetric synthesis ,natural compounds ,Chemical technology ,TP1-1185 ,Chemistry ,QD1-999 - Abstract
2,3-dihydroxy-2-methylbutyric acid, also known as 2,3-dimethylglyceric acid, constitutes the acyl and/or the alcoholic moiety of many bioactive natural esters. Herein, we describe a chemoenzymatic methodology which gives access to all the four possible stereoisomers of the 2,3-dimethylglyceric acid ethyl ester. The racemic ethyl α-acetolactate, produced by the N-heterocycle carbene (NHC)-catalyzed coupling of ethyl pyruvate and methylacetoin was employed as the starting material. The racemic mixture was resolved through (S)-selective reductions, promoted by the acetylacetoin reductase (AAR) affording the resulting ethyl (2R,3S)-2,3-dimethylglycerate; the isolated remaining (S)-ethyl α-acetolactate was successively treated with baker’s yeast to obtain the corresponding (2S,3S) stereoisomer. syn-2,3-Dimethylgliceric acid ethyl ester afforded by reducing the rac-α-acetolactate with NaBH4 in the presence of ZnCl2 was kinetically resolved through selective acetylation with lipase B from Candida antarctica (CAL-B) and vinyl acetate to access to (2S,3R) stereoisomer. Finally, the (2R,3R) stereoisomer, was prepared by C3 epimerization of the (2R,3S) stereoisomer recovered from the above kinetic resolution, achieved through the TEMPO-mediated oxidation, followed by the reduction of the produced ketone with NaBH4. The resulting 2,3-dimethylglycertate enriched in the (2R,3R) stereoisomer was submitted to stereospecicific acetylation with vinyl acetate and CAL-B in order to separate the major stereoisomer. The entire procedure enabled conversion of the racemic α-acetolactate into the four enantiopure stereoisomers of the ethyl 2,3-dihydroxy-2-methylbutyrate with the following overall yields: 42% for the (2R,3S), 40% for the (2S,3S), 42% for the (2S,3R) and 20% for the (2R,3R).
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- 2021
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15. Glyceric Prodrug of Ursodeoxycholic Acid (UDCA): Novozym 435-Catalyzed Synthesis of UDCA-Monoglyceride
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Federico Zappaterra, Stefania Costa, Daniela Summa, Bruno Semeraro, Virginia Cristofori, Claudio Trapella, and Elena Tamburini
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ursodeoxycholic acid ,monoglyceride ,esterification ,CALB ,prodrug ,Organic chemistry ,QD241-441 - Abstract
Bile acids (BAs) are a family of steroids synthesized from cholesterol in the liver. Among bile acids, ursodeoxycholic acid (UDCA) is the drug of choice for treating primary biliary cirrhosis and dissolving cholesterol gallstones. The clinical effectiveness of UDCA includes its choleretic activity, the capability to inhibit hydrophobic bile acid absorption by the intestine under cholestatic conditions, reducing cholangiocyte injury, stimulation of impaired biliary output, and inhibition of hepatocyte apoptosis. Despite its clinical effectiveness, UDCA is poorly soluble in the gastro-duodeno-jejunal contents, and pharmacological doses of UDCA are not readily soluble in the stomach and intestine, resulting in incomplete absorption. Indeed, the solubility of 20 mg/L greatly limits the bioavailability of UDCA. Since the bioavailability of drug products plays a critical role in the design of oral administration dosages, we investigated the enzymatic esterification of UDCA as a strategy of hydrophilization. Therefore, we decided to enzymatically synthesize a glyceric ester of UDCA bile acid to produce a more water-soluble molecule. The esterification reactions between UDCA and glycerol were performed with an immobilized lipase B from Candida antarctica (Novozym 435) in solvent-free and solvent-assisted systems. The characterization of the UDCA-monoglyceride, enzymatically synthesized, has been performed by 1H-NMR, 13C-NMR, COSY, HSQC, HMBC, IR, and MS spectroscopy.
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- 2021
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16. Worsening of the Toxic Effects of (±)Cis-4,4′-DMAR Following Its Co-Administration with (±)Trans-4,4′-DMAR: Neuro-Behavioural, Physiological, Immunohistochemical and Metabolic Studies in Mice
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Micaela Tirri, Paolo Frisoni, Sabrine Bilel, Raffaella Arfè, Claudio Trapella, Anna Fantinati, Giorgia Corli, Beatrice Marchetti, Fabio De-Giorgio, Cristian Camuto, Monica Mazzarino, Rosa Maria Gaudio, Giovanni Serpelloni, Fabrizio Schifano, Francesco Botrè, and Matteo Marti
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4-4′-DMAR ,immunohistochemistry ,drug metabolism ,hyperthermia ,novel psychoactive substances ,stimulant ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
4,4’-Dimethylaminorex (4,4’-DMAR) is a new synthetic stimulant, and only a little information has been made available so far regarding its pharmaco-toxicological effects. The aim of this study was to investigate the effects of the systemic administration of both the single (±)cis (0.1–60 mg/kg) and (±)trans (30 and 60 mg/kg) stereoisomers and their co-administration (e.g., (±)cis at 1, 10 or 60 mg/kg + (±)trans at 30 mg/kg) in mice. Moreover, we investigated the effect of 4,4′-DMAR on the expression of markers of oxidative/nitrosative stress (8-OHdG, iNOS, NT and NOX2), apoptosis (Smac/DIABLO and NF-κB), and heat shock proteins (HSP27, HSP70, HSP90) in the cerebral cortex. Our study demonstrated that the (±)cis stereoisomer dose-dependently induced psychomotor agitation, sweating, salivation, hyperthermia, stimulated aggression, convulsions and death. Conversely, the (±)trans stereoisomer was ineffective whilst the stereoisomers’ co-administration resulted in a worsening of the toxic (±)cis stereoisomer effects. This trend of responses was confirmed by immunohistochemical analysis on the cortex. Finally, we investigated the potentially toxic effects of stereoisomer co-administration by studying urinary excretion. The excretion study showed that the (±)trans stereoisomer reduced the metabolism of the (±)cis form and increased its amount in the urine, possibly reflecting its increased plasma levels and, therefore, the worsening of its toxicity.
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- 2021
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17. Design of Liposomes Carrying HelixComplex Snail Mucus: Preliminary Studies
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Andrea Alogna, Valentina Gentili, Claudio Trapella, Supandeep Singh Hallan, Maddalena Sguizzato, Giovanni Strazzabosco, Mercedes Fernández, Rita Cortesi, Roberta Rizzo, and Daria Bortolotti
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slime mucus ,HelixComplex ,liposomes ,MTT test ,drug delivery ,Organic chemistry ,QD241-441 - Abstract
In recent decades liposomes have been used in different field thanks to their ability to act as a vehicle for a wide range of biomolecules, their great versatility and their easy production. The aim of this study was to evaluate liposomes as a vehicle for the actives present in the HelixComplex (HC) snail mucus for topical delivery. Liposomes composed of a mixture of phosphatidylcholine, cholesterol and octadecylamine were prepared with and without HC (empty liposomes) and their biological efficacy was tested by evaluating cell viability and migration. HC-loaded liposomes (LHC) were stable throughout 60 days of observation, and showed interesting effects on wound healing reconstitution. In particular, we observed that 25 µg/mL LHC were already able to induce a higher cell monolayer reconstitution in comparison to the untreated samples and HC treated samples after only 4 h (28% versus 10% and 7%, p = 0.03 and p= 0.003, respectively). The effect was more evident at 24 h in comparison with the untreated control (54% versus 21.2% and 41.6%, p = 0.006 and p = NS, respectively). These results represent a preliminary, but promising, novelty in the delivery strategy of the actives present in the HelixComplex mucus.
- Published
- 2021
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18. A diastereoselective synthesis of Cebranopadol, a novel analgesic showing NOP/mu mixed agonism
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Anna Fantinati, Sara Bianco, Remo Guerrini, Severo Salvadori, Salvatore Pacifico, Maria Camilla Cerlesi, Girolamo Calo, and Claudio Trapella
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Medicine ,Science - Abstract
Abstract A diastereoselective synthesis of the title compound as a single E diastereomer has been efficiently accomplished by assembling the featured pyrano-indole scaffold of the spiro[cyclohexane-dihydropyrano[3,4-b]-indole]-amine framework through an oxa-Pictet-Spengler reaction, promoted by a cheap and green Zeolite catalyst. Basic pharmacological experiments demonstrate that Cebranopadol acts as a mixed nociception/orphanin FQ (NOP) and mu (MOP) opioid receptor agonist useful for treatment of chronic pain.
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- 2017
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19. Naphthoquinone amino acid derivatives, synthesis and biological activity as proteasome inhibitors
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Mauro Marastoni, Claudio Trapella, Alessandra Scotti, Anna Fantinati, Valeria Ferretti, Erika Marzola, Gallerani Eleonora, Riccardo Gavioli, and Delia Preti
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Proteasome ,naphthoquinone ,amino acid derivatives ,post-acidic inhibition ,Therapeutics. Pharmacology ,RM1-950 - Abstract
The ubiquitin-proteasome system has been largely investigated for its key role in protein degradation mechanisms that regulate both apoptosis and cell division. Because of their antitumour activity, different classes of proteasome inhibitors have been identified to date. Some of these compounds are currently employed in the clinical treatment of several types of cancer among which multiple myeloma. Here, we describe the design, chemistry, biological activity and modelling studies of a large series of amino acid derivatives linked to a naphthoquinone pharmacophoric group through variable spacers. Some analogues showed interesting inhibitory potency for the β1 and β5 subunits of the proteasome with IC50 values in the sub-µm range.
- Published
- 2017
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20. Conjugation of LasR Quorum-Sensing Inhibitors with Ciprofloxacin Decreases the Antibiotic Tolerance of P. aeruginosa Clinical Strains
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Daria Bortolotti, Claudio Trapella, Alessandra Bragonzi, Paolo Marchetti, Vinicio Zanirato, Andrea Alogna, Valentina Gentili, Carlo Cervellati, Giuseppe Valacchi, Mariangela Sicolo, Giulia Turrin, Anna Fantinati, Dario Di Luca, and Roberta Rizzo
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Chemistry ,QD1-999 - Abstract
Pseudomonas aeruginosa is a Gram-negative bacterium that commonly infects subjects with weakened immune system causing deadly infections above all at pulmonary level. During infection, P. aeruginosa produces a well-organized bacterial structure, called biofilm, activating the quorum-sensing (QS) signaling, a mechanism of gene regulation. In this work, we synthesized already known QS inhibitors (QSi) designed on the scaffold of the N-(3-oxododecanoyl) homoserine lactone (3O-C12-HSL) QS molecule and conjugated them with ciprofloxacin to inhibit P. aeruginosa biofilm formation and increase the antibiotic susceptibility of clinical strains. We identified, for the first time, a QSi conjugated with ciprofloxacin (ET37), that is able to reduce the formation of biofilm and the onset of tolerant clones in P. aeruginosa clinical strains. This compound could have a wide application in clinical setting. The possibility to affect biofilm formation in chronically infected patients, such as patients affected by cystic fibrosis, and to reduce the onset of ciprofloxacin resistance would improve patient healing and allow to decrease antibiotic drug dosage.
- Published
- 2019
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21. An Alternative Enzymatic Route to the Ergogenic Ketone Body Ester (R)-3-Hydroxybutyl (R)-3-Hydroxybutyrate
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Ferdinando Zaccone, Valentina Venturi, Pier Paolo Giovannini, Claudio Trapella, Marco Narducci, Hugues Fournier, and Anna Fantinati
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ketone body ester ,lipase ,kinetic resolution ,asymmetric synthesis ,configuration inversion ,Chemical technology ,TP1-1185 ,Chemistry ,QD1-999 - Abstract
Recent studies have highlighted the therapeutic and ergogenic potential of the ketone body ester, (R)-3-hydroxybutyl-(R)-3-hydroxybutyrate. In the present work, the enzymatic synthesis of this biological active compound is reported. The (R)-3-hydroxybutyl-(R)-3-hydroxybutyrate has been produced through the transesterification of racemic ethyl 3-hydroxybutyrate with (R)-1,3-butanediol by exploiting the selectivity of Candida antarctica lipase B (CAL-B). The needed (R)-1,3-butanediol was in turn obtained from the kinetic resolution of the racemate achieved by acetylation with vinyl acetate, also in this case, thanks to the enantioselectivity of the CAL-B used as catalyst. Finally, the stereochemical inversion of the unreacted (S) enantiomers of the ethyl 3-hydroxybutyate and 1,3-butanediol accomplished by known procedure allowed to increase the overall yield of the synthetic pathway by incorporating up to 70% of the starting racemic reagents into the final product.
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- 2021
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22. Design of Nanosystems for the Delivery of Quorum Sensing Inhibitors: A Preliminary Study
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Supandeep Singh Hallan, Paolo Marchetti, Daria Bortolotti, Maddalena Sguizzato, Elisabetta Esposito, Paolo Mariani, Claudio Trapella, Roberta Rizzo, and Rita Cortesi
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nanotechnological systems ,liposomes ,QS inhibitors ,drug delivery ,biofilm ,MTT test ,Organic chemistry ,QD241-441 - Abstract
Biofilm production is regulated by the Quorum Sensing system. Nowadays, Quorum Sensing represents an appealing target to design new compounds to increase antibiotics effects and avoid development of antibiotics multiresistance. In this research the use of liposomes to target two novel synthetic biofilm inhibitors is presented, focusing on a preformulation study to select a liposome composition for in vitro test. Five different liposome (LP) formulations, composed of phosphatidyl choline, cholesterol and charged surfactant (2:1:1, molar ratio) have been prepared by direct hydration and extrusion. As charged surfactants dicetyl phosphate didecyldimethylammonium chloride, di isobutyl phenoxy ethyl dimethyl benzyl ammonium chloride and stearylamine (SA) and have been used. Liposome charge, size and morphology were investigated by zeta potential, photon correlation spectroscopy, small angle x-ray spectroscopy and electron microscopy. LP-SA was selected for the loading of biofilm inhibitors and subjected to high performance liquid chromatography for entrapment capacity evaluation. LP-SA loaded inhibitors showed a higher diameter (223.6 nm) as compared to unloaded ones (205.7 nm) and a dose-dependent anti-biofilm effect mainly after 48 h of treatment, while free biofilm inhibitors loose activity. In conclusion, our data supported the use of liposomes as a strategy to enhance biofilm inhibitors effect.
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- 2020
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23. Discovery of Novel Fetal Hemoglobin Inducers through Small Chemical Library Screening
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Giulia Breveglieri, Salvatore Pacifico, Cristina Zuccato, Lucia Carmela Cosenza, Shaiq Sultan, Elisabetta D’Aversa, Roberto Gambari, Delia Preti, Claudio Trapella, Remo Guerrini, and Monica Borgatti
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hemoglobinopathies ,β-thalassemia ,sickle cell disease ,fetal hemoglobin ,chemical screening ,compound library ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
The screening of chemical libraries based on cellular biosensors is a useful approach to identify new hits for novel therapeutic targets involved in rare genetic pathologies, such as β-thalassemia and sickle cell disease. In particular, pharmacologically mediated stimulation of human γ-globin gene expression, and increase of fetal hemoglobin (HbF) production, have been suggested as potential therapeutic strategies for these hemoglobinopathies. In this article, we screened a small chemical library, constituted of 150 compounds, using the cellular biosensor K562.GR, carrying enhanced green fluorescence protein (EGFP) and red fluorescence protein (RFP) genes under the control of the human γ-globin and β-globin gene promoters, respectively. Then the identified compounds were analyzed as HbF inducers on primary cell cultures, obtained from β-thalassemia patients, confirming their activity as HbF inducers, and suggesting these molecules as lead compounds for further chemical and biological investigations.
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- 2020
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24. Enzymatic Esterification as Potential Strategy to Enhance the Sorbic Acid Behavior as Food and Beverage Preservative
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Federico Zappaterra, Daniela Summa, Bruno Semeraro, Raissa Buzzi, Claudio Trapella, Miguel Ladero, Stefania Costa, and Elena Tamburini
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sorbic acid ,glycerol ,esterification ,lipase ,CALB ,antimicrobial ,Fermentation industries. Beverages. Alcohol ,TP500-660 - Abstract
Sorbic acid is the most commonly used preservative in the food industry. The antimicrobial inhibition of sorbic acid could be influenced by its lipophilic nature, which reduces its use in hydrophilic food formulations. Reactions between sorbic acid and glycerol catalyzed by lipases were studied in order to develop a novel sorbic acid derivate with a promising hydrophilic profile. The esterification reaction between sorbic acid and glycerol in a solvent-free system were performed with an immobilized lipase B from Candida antarctica (CALB). The glycerol sorbate product has been tested against S. griseus bacterium and Saccharomyces cerevisiae yeast. Results indicate that the esterification of sorbic acid with glycerol does improve its antimicrobial properties against Saccharomyces cerevisie. The reported results demonstrate that esterification can be used as a strategy to improve the antimicrobial activity of sorbic acid.
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- 2020
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25. NOP receptor pharmacological profile - A dynamic mass redistribution study.
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Davide Malfacini, Katharina Simon, Claudio Trapella, Remo Guerrini, Nurulain T Zaveri, Evi Kostenis, and Girolamo Calo'
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Medicine ,Science - Abstract
The Nociceptin/Orphanin FQ (N/OFQ) peptide NOP receptor is coupled to pertussis toxin (PTX)-sensitive G proteins (Gi/o) whose activation leads to the inhibition of both cAMP production and calcium channel activity, and to the stimulation of potassium currents. The label free dynamic mass redistribution (DMR) approach has been demonstrated useful for investigating the pharmacological profile of G protein-coupled receptors. Herein, we employ DMR technology to systematically characterize the pharmacology of a large panel of NOP receptor ligands. These are of peptide and non-peptide nature and display varying degrees of receptor efficacy, ranging from full agonism to pure antagonism. Using Chinese hamster ovary (CHO) cells expressing the human NOP receptor we provide rank orders of potency for full and partial agonists as well as apparent affinities for selective antagonists. We find the pharmacological profile of NOP receptor ligands to be similar but not identical to values reported in the literature using canonical assays for Gi/o-coupled receptors. Our data demonstrate that holistic label-free DMR detection can be successfully used to investigate the pharmacology of the NOP receptor and to characterize the cellular effects of novel NOP receptor ligands.
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- 2018
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26. Identification of small-molecule urea derivatives as PTPC modulators targeting the c subunit of F
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Anna, Fantinati, Giampaolo, Morciano, Giulia, Turrin, Gaia, Pedriali, Salvatore, Pacifico, Delia, Preti, Valentina, Albanese, Davide, Illuminati, Virginia, Cristofori, Carlotta, Giorgi, Elena, Tremoli, Paolo, Pinton, and Claudio, Trapella
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Adenosine Triphosphate ,Azirines ,Phosphatidylcholines ,Urea ,Mitochondrial Membrane Transport Proteins ,Mitochondria - Abstract
Maintaining a high percentage of living and functional cells in those pathologies in which excessive cell death occurs, such as neurodegenerative disorders and cardiovascular diseases, is one of the most intriguing challenges in the field of biochemical research for drug discovery. Here, mitochondrial permeability transition-driven regulated cell death is the main mechanism of mitochondrial impairment and cell fate; this pathway is still lacking of satisfying pharmacological treatments to counteract its becoming; for this reason, it needs continuous and intense research to find new compounds as modulator of the permeability transition pore complex (PTPC) activity. In this study, we report the identification of small-molecule urea derivatives able to inhibit PTPC opening following calcium overload and selected for future use in cytoprotection.
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- 2022
27. Xylitol as a Hydrophilization Moiety for a Biocatalytically Synthesized Ibuprofen Prodrug
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Stefania COSTA, Federico Zappaterra, Daniela Summa, Claudio Trapella, Virginia Cristofori, Ilaria Lampronti, Given Names Deactivated Family Name Deactivated, and Elena Tamburini
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Cystic Fibrosis ,Biological Availability ,Ibuprofen ,Catalysis ,NO ,Cell Line ,Inorganic Chemistry ,Cystic fibrosis (CF) ,Humans ,Prodrugs ,Physical and Theoretical Chemistry ,Prodrug ,Molecular Biology ,Xylitol ,Spectroscopy ,Analgesics ,Esterification ,organic chemicals ,Anti-Inflammatory Agents, Non-Steroidal ,Organic Chemistry ,IB3‐1 ,Water ,Esters ,General Medicine ,CALB ,Computer Science Applications ,Solubility ,Biocatalysis ,ibuprofen ,xylitol ,prodrug ,esterification ,cystic fibrosis (CF) ,IB3-1 - Abstract
Biocatalyzed synthesis can be exploited to produce high-value products, such as prodrugs. The replacement of chemical approaches with biocatalytic processes is advantageous in terms of environmental prevention, embracing the principles of green chemistry. In this work, we propose the covalent attachment of xylitol to ibuprofen to produce an IBU-xylitol ester prodrug. Xylitol was chosen as a hydrophilizer for the final prodrug, enhancing the water solubility of ibuprofen. Ibuprofen is a nonsteroidal anti-inflammatory drug (NSAID) extensively used as an analgesic, anti-inflammatory, and antipyretic. Despite being the third-most-prescribed medicine in the world, the aqueous solubility of ibuprofen is just 21 mg/L. This poor water solubility greatly limits the bioavailability of ibuprofen. We aimed to functionalize ibuprofen with xylitol using the reusable immobilized N435 biocatalyst. Instead of a biphasic media, we proposed a monophasic reaction environment. The characterization of the IBU-xylitol ester was performed by 1H, 13C-NMR, DEPT, COSY, HMQC, HMBC, FTIR, and MS spectroscopy. Preliminary in vitro tests showed that this enzymatically synthesized prodrug of ibuprofen reduced the expression of the interleukin 8 genes in human bronchial epithelial cells (IB3-1) from cystic fibrosis (CF) patients.
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- 2022
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28. Identification of Small-Molecule Urea Derivatives as Ptpc Modulators
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Anna Fantinati, Giampaolo Morciano, Giulia Turrin, Gaia Pedriali, Salvatore Pacifico, Delia Preti, Valentina Albanese, Davide Illuminati, Virginia Cristofori, Carlotta Giorgi, Elena Tremoli, Paolo Pinton, and Claudio Trapella
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History ,Polymers and Plastics ,Business and International Management ,Industrial and Manufacturing Engineering - Published
- 2022
29. Synthesis of 2,6-Dimethyltyrosine-Like Amino Acids through Pinacolinamide-Enabled C-H Dimethylation of 4-Dibenzylamino Phenylalanine
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Davide Illuminati, Anna Fantinati, Tiziano De Ventura, Daniela Perrone, Chiara Sturaro, Valentina Albanese, Erika Marzola, Virginia Cristofori, Julie Oble, Giovanni Poli, and Claudio Trapella
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Phenylalanine ,Organic Chemistry ,Tyrosine ,Amino Acids ,NO - Abstract
The synthesis of a small library of
- Published
- 2022
30. Chemoenzymatic Stereodivergent Synthesis of All the Possible Stereoisomers of the 2,3-Dimethylglyceric Acid Ethyl Ester
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Anna Fantinati, Lindomar Alberto Lerin, Olga Bortolini, Francesco Presini, Claudio Trapella, Pier Paolo Giovannini, Graziano Di Carmine, and Virginia Cristofori
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Ketone ,biocatalysis ,Stereochemistry ,asymmetric synthesis ,stereodivergent synthesis ,natural compounds ,TP1-1185 ,PE4_12 ,Catalysis ,Kinetic resolution ,chemistry.chemical_compound ,Vinyl acetate ,Physical and Theoretical Chemistry ,QD1-999 ,chemistry.chemical_classification ,biology ,Chemical technology ,Enantioselective synthesis ,biocatalysis, stereodivergent synthesis, asymmetric synthesis, natural compounds ,Ambientale ,biology.organism_classification ,PE5_17 ,Chemistry ,Enantiopure drug ,chemistry ,Racemic mixture ,Candida antarctica ,Epimer - Abstract
2,3-dihydroxy-2-methylbutyric acid, also known as 2,3-dimethylglyceric acid, constitutes the acyl and/or the alcoholic moiety of many bioactive natural esters. Herein, we describe a chemoenzymatic methodology which gives access to all the four possible stereoisomers of the 2,3-dimethylglyceric acid ethyl ester. The racemic ethyl α-acetolactate, produced by the N-heterocycle carbene (NHC)-catalyzed coupling of ethyl pyruvate and methylacetoin was employed as the starting material. The racemic mixture was resolved through (S)-selective reductions, promoted by the acetylacetoin reductase (AAR) affording the resulting ethyl (2R,3S)-2,3-dimethylglycerate; the isolated remaining (S)-ethyl α-acetolactate was successively treated with baker’s yeast to obtain the corresponding (2S,3S) stereoisomer. syn-2,3-Dimethylgliceric acid ethyl ester afforded by reducing the rac-α-acetolactate with NaBH4 in the presence of ZnCl2 was kinetically resolved through selective acetylation with lipase B from Candida antarctica (CAL-B) and vinyl acetate to access to (2S,3R) stereoisomer. Finally, the (2R,3R) stereoisomer, was prepared by C3 epimerization of the (2R,3S) stereoisomer recovered from the above kinetic resolution, achieved through the TEMPO-mediated oxidation, followed by the reduction of the produced ketone with NaBH4. The resulting 2,3-dimethylglycertate enriched in the (2R,3R) stereoisomer was submitted to stereospecicific acetylation with vinyl acetate and CAL-B in order to separate the major stereoisomer. The entire procedure enabled conversion of the racemic α-acetolactate into the four enantiopure stereoisomers of the ethyl 2,3-dihydroxy-2-methylbutyrate with the following overall yields: 42% for the (2R,3S), 40% for the (2S,3S), 42% for the (2S,3R) and 20% for the (2R,3R).
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- 2021
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31. APPLICATIONS OF A NOVEL CONTRAST AGENT IN X-RAY IMAGING OF ARTICULAR CARTILAGE: A PRELIMINARY EXPERIENCE
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Simone Fantoni, Paolo Cardarelli, Angelo Taibi, Virginia Cristofori, Claudio Trapella, Armando Bazzani, Ilenia Gabucci, Marta Assenza, Daniele Conti, and Fabio Baruffaldi
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Biophysics ,General Physics and Astronomy ,Radiology, Nuclear Medicine and imaging ,General Medicine - Published
- 2022
32. Design and Synthesis of 99mTcN-Labeled Dextran-Mannose Derivatives for Sentinel Lymph Node Detection
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Alessandra Boschi, Micòl Pasquali, Claudio Trapella, Alessandro Massi, Petra Martini, Adriano Duatti, Remo Guerrini, Vinicio Zanirato, Anna Fantinati, Erika Marzola, Melchiore Giganti, and Licia Uccelli
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sentinel lymph node ,dextran ,mannose ,99mTc-radiopharmaceuticals ,Medicine ,Pharmacy and materia medica ,RS1-441 - Abstract
Background: New approaches based on the receptor-targeted molecular interaction have been recently developed with the aim to investigate specific probes for sentinel lymph nodes. In particular, the mannose receptors expressed by lymph node macrophages became an attractive target and different multifunctional mannose derivate ligands for the labeling with 99mTc have been developed. In this study, we report the synthesis of a specific class of dextran-based, macromolecular, multifunctional ligands specially designed for labeling with the highly stable [99mTc≡N]2+ core. Methods: The ligands have been obtained by appending to a macromolecular dextran scaffold pendant arms bearing a chelating moiety for the metallic group and a mannosyl residue for allowing the interaction of the resulting macromolecular 99mTc conjugate with specific receptors on the external membrane of macrophages. Two different chelating systems have been selected, S-methyl dithiocarbazate [H2N‒NH‒C(=S)SCH3=HDTCZ] and a sequence of two cysteine residues, that in combination with a monophosphine coligand, are able to bind the [99mTc≡N]2+ core. Conclusions: High-specific-activity labeling has been obtained by simple mixing and heating of the [99mTc≡N]2+ group with the new mannose-dextran derivatives.
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- 2018
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33. Nociceptin/orphanin FQ receptor blockade attenuates MPTP-induced parkinsonism
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Riccardo Viaro, Rosario Sanchez-Pernaute, Matteo Marti, Claudio Trapella, Ole Isacson, and Michele Morari
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J-113397 ,L-DOPA ,MPTP ,Nociceptin/orphanin FQ ,NOP−/− mice ,NOP receptor ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Endogenous nociceptin/orphanin FQ (N/OFQ) inhibits the activity of dopamine neurons in the substantia nigra and affects motor behavior. In this study we investigated whether a N/OFQ receptor (NOP) antagonist, J-113397, can modify movement in naive mice and nonhuman primates and attenuate motor deficits in MPTP-treated parkinsonian animals. J-113397 facilitated motor activity in naïve mice at low doses (0.1–1 mg/kg) and inhibited it at higher ones (10 mg/kg). Likewise, in MPTP-treated mice, J-113397 reversed motor deficit at 0.01 mg/kg but worsened hypokinesia at higher doses (1 mg/kg). In naïve nonhuman primates, J-113397, ineffective up to 1 mg/kg, produced inconsistent motor improvements at 3 mg/kg. Conversely, in parkinsonian primates J-113397 (0.01 mg/kg) reversed parkinsonism, being most effective against hypokinesia. We conclude that endogenous N/OFQ modulates motor activity in mice and nonhuman primates and contributes to parkinsonian symptoms in MPTP-treated animals. NOP receptor antagonists may represent a novel approach to Parkinson's disease.
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- 2008
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34. Functional Profile of Systemic and Intrathecal Cebranopadol in Non-human Primates
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Claudio Trapella, Girolamo Calo, Mei-Chuan Ko, Fang-Chi Hsu, Huiping Ding, and Norikazu Kiguchi
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0301 basic medicine ,Agonist ,Male ,Indoles ,Spinal ,medicine.drug_class ,Receptors, Opioid, mu ,Opioid ,Pharmacology ,Partial agonist ,Nociceptin Receptor ,Article ,Fentanyl ,NO ,Injections ,Dose-Response Relationship ,03 medical and health sciences ,0302 clinical medicine ,Opioid receptor ,Receptors ,Medicine ,LS5_5 ,LS7_3 ,Animals ,Humans ,Respiratory function ,Spiro Compounds ,Injections, Spinal ,Pain Measurement ,Analgesics ,Dose-Response Relationship, Drug ,business.industry ,Cebranopadol ,Macaca mulatta ,Analgesics, Opioid ,Nociceptin receptor ,030104 developmental biology ,Anesthesiology and Pain Medicine ,Opioid Peptides ,mu ,Receptors, Opioid ,Morphine ,Female ,Drug ,business ,030217 neurology & neurosurgery ,medicine.drug - Abstract
Background Cebranopadol, a mixed nociceptin/opioid receptor full agonist, can effectively relieve pain in rodents and humans. However, it is unclear to what degree different opioid receptor subtypes contribute to its antinociception and whether cebranopadol lacks acute opioid-associated side effects in primates. The authors hypothesized that coactivation of nociceptin receptors and μ receptors produces analgesia with reduced side effects in nonhuman primates. Methods The antinociceptive, reinforcing, respiratory-depressant, and pruritic effects of cebranopadol in adult rhesus monkeys (n = 22) were compared with μ receptor agonists fentanyl and morphine using assays, including acute thermal nociception, IV drug self-administration, telemetric measurement of respiratory function, and itch-scratching responses. Results Subcutaneous cebranopadol (ED50, 2.9 [95% CI, 1.8 to 4.6] μg/kg) potently produced antinociception compared to fentanyl (15.8 [14.6 to 17.1] μg/kg). Pretreatment with antagonists selective for nociceptin and μ receptors, but not δ and κ receptor antagonists, caused rightward shifts of the antinociceptive dose–response curve of cebranopadol with dose ratios of 2 and 9, respectively. Cebranopadol produced reinforcing effects comparable to fentanyl, but with decreased reinforcing strength, i.e., cebranopadol (mean ± SD, 7 ± 3 injections) versus fentanyl (12 ± 3 injections) determined by a progressive-ratio schedule of reinforcement. Unlike fentanyl (8 ± 2 breaths/min), systemic cebranopadol at higher doses did not decrease the respiratory rate (17 ± 2 breaths/min). Intrathecal cebranopadol (1 μg) exerted full antinociception with minimal scratching responses (231 ± 137 scratches) in contrast to intrathecal morphine (30 μg; 3,009 ± 1,474 scratches). Conclusions In nonhuman primates, the μ receptor mainly contributed to cebranopadol-induced antinociception. Similar to nociceptin/μ receptor partial agonists, cebranopadol displayed reduced side effects, such as a lack of respiratory depression and pruritus. Although cebranopadol showed reduced reinforcing strength, its detectable reinforcing effects and strength warrant caution, which is critical for the development and clinical use of cebranopadol. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New
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- 2021
35. Design of Liposomes Carrying HelixComplex Snail Mucus: Preliminary Studies
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Giovanni Strazzabosco, Maddalena Sguizzato, Supandeep Singh Hallan, Roberta Rizzo, Valentina Gentili, M. Fernandez, Andrea Alogna, Daria Bortolotti, Claudio Trapella, and Rita Cortesi
- Subjects
0301 basic medicine ,liposomes ,Spectrophotometry, Infrared ,Snails ,Cell ,HelixComplex ,Pharmaceutical Science ,MTT test ,Article ,Cell Line ,NO ,Analytical Chemistry ,03 medical and health sciences ,chemistry.chemical_compound ,QD241-441 ,0302 clinical medicine ,Phosphatidylcholine ,Drug Discovery ,medicine ,Animals ,Freeze Fracturing ,Humans ,LS7_3 ,Viability assay ,Physical and Theoretical Chemistry ,slime mucus ,Wound Healing ,Liposome ,Chromatography ,Cell Death ,Cholesterol ,Organic Chemistry ,drug delivery ,Fibroblasts ,Lipids ,Mucus ,030104 developmental biology ,medicine.anatomical_structure ,chemistry ,Chemistry (miscellaneous) ,030220 oncology & carcinogenesis ,Drug delivery ,Molecular Medicine ,Wound healing - Abstract
In recent decades liposomes have been used in different field thanks to their ability to act as a vehicle for a wide range of biomolecules, their great versatility and their easy production. The aim of this study was to evaluate liposomes as a vehicle for the actives present in the HelixComplex (HC) snail mucus for topical delivery. Liposomes composed of a mixture of phosphatidylcholine, cholesterol and octadecylamine were prepared with and without HC (empty liposomes) and their biological efficacy was tested by evaluating cell viability and migration. HC-loaded liposomes (LHC) were stable throughout 60 days of observation, and showed interesting effects on wound healing reconstitution. In particular, we observed that 25 µg/mL LHC were already able to induce a higher cell monolayer reconstitution in comparison to the untreated samples and HC treated samples after only 4 h (28% versus 10% and 7%, p = 0.03 and p= 0.003, respectively). The effect was more evident at 24 h in comparison with the untreated control (54% versus 21.2% and 41.6%, p = 0.006 and p = NS, respectively). These results represent a preliminary, but promising, novelty in the delivery strategy of the actives present in the HelixComplex mucus.
- Published
- 2021
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36. In vitro and in vivo pharmaco-dynamic study of the novel fentanyl derivatives: Acrylfentanyl, Ocfentanyl and Furanylfentanyl
- Author
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Sabrine Bilel, Joaquim Azevedo Neto, Raffaella Arfè, Micaela Tirri, Rosa Maria Gaudio, Anna Fantinati, Tatiana Bernardi, Federica Boccuto, Beatrice Marchetti, Giorgia Corli, Giovanni Serpelloni, Fabio De-Giorgio, Davide Malfacini, Claudio Trapella, Girolamo Calo’, and Matteo Marti
- Subjects
Pharmacology ,Male ,Novel psychoactive substances mu opioid receptor ,Naloxone ,Receptors, Opioid, mu ,Pain ,Acrylfentanyl ,Analgesia ,Cardiorespiratory changes ,Fentanyl ,Furanylfentanyl ,Ocfentanyl ,β-arrestin 2 ,beta-Arrestin 2 ,Analgesics, Opioid ,Cellular and Molecular Neuroscience ,Mice ,Receptors, Opioid ,Animals ,Furans - Abstract
Fentanyl derivatives (FENS) belongs to the class of Novel Synthetic Opioids that emerged in the illegal drug market of New Psychoactive Substances (NPS). These substances have been implicated in many cases of intoxication and death with overdose worldwide. Therefore, the aim of this study is to investigate the pharmaco-dynamic profiles of three fentanyl (FENT) analogues: Acrylfentanyl (ACRYLF), Ocfentanyl (OCF) and Furanylfentanyl (FUF). In vitro, we measured FENS opioid receptor efficacy, potency, and selectivity in calcium mobilization studies performed in cells coexpressing opioid receptors and chimeric G proteins and their capability to promote the interaction of the mu receptor with G protein and β-arrestin 2 in bioluminescence resonance energy transfer (BRET) studies. In vivo, we investigated the acute effects of the systemic administration of ACRYLF, OCF and FUF (0.01-15 mg/kg i.p.) on mechanical and thermal analgesia, motor impairment, grip strength and cardiorespiratory changes in CD-1 male mice. Opioid receptor specificity was investigated in vivo using naloxone (NLX; 6 mg/kg i.p) pre-treatment. In vitro, the three FENS were able to activate the mu opioid receptor in a concentration dependent manner with following rank order potency: FUF FENT=OCF ACRYLF. All compounds were able to elicit maximal effects similar to that of dermorphin, with the exception of FUF which displayed lower maximal effects thus behaving as a partial agonist. In the BRET G-protein assay, all compounds behaved as partial agonists for the β-arrestin 2 pathway in comparison with dermorphin, whereas FUF did not promote β-arrestin 2 recruitment, behaving as an antagonist. In vivo, all the compounds increased mechanical and thermal analgesia with following rank order potency ACRYLF = FENT FUF OCF and impaired motor and cardiorespiratory parameters. Among the substances tested, FUF showed lower potency for cardiorespiratory and motor effects. These findings reveal the risks associated with the use of FENS and the importance of studying the pharmaco-dynamic properties of these drugs to better understand possible therapeutic interventions in the case of toxicity.
- Published
- 2021
37. Novel Mixed NOP/Opioid Receptor Peptide Agonists
- Author
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Erika Marzola, Chiara Ruzza, Davide Illuminati, Salvatore Pacifico, Delia Preti, Claudio Trapella, Davide Malfacini, Ettore Lo Cascio, Valentina Albanese, Martina Marangoni, Remo Guerrini, Alessandro Arcovito, Martina Fabbri, Davide Fattori, Victor A D Holanda, Romina Nassini, Chiara Sturaro, Girolamo Calò, Federica Ferrari, and Stefano Della Longa
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Male ,Opiod receptors ,NOP, MOP, Nociceptin ,NOP ,Receptors, Opioid, mu ,Peptide ,Pharmacology ,01 natural sciences ,Nociceptin Receptor ,Opioid receptor ,Drug Discovery ,Receptors ,Receptor ,chemistry.chemical_classification ,Animals ,Binding Sites ,Cough ,Disease Models, Animal ,Guinea Pigs ,Humans ,Hydrophobic and Hydrophilic Interactions ,Molecular Dynamics Simulation ,Peptides ,Receptors, Opioid ,Recombinant Proteins ,Structure-Activity Relationship ,0303 health sciences ,Chemistry ,Nociceptin ,Nociceptin receptor ,Molecular Medicine ,μ-opioid receptor ,medicine.drug ,Agonist ,medicine.drug_class ,Opioid ,Article ,NO ,03 medical and health sciences ,medicine ,Settore BIO/10 - BIOCHIMICA ,030304 developmental biology ,MOP ,Animal ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,mu ,Disease Models - Abstract
The nociceptin/orphanin FQ (N/OFQ)/N/OFQ receptor (NOP) system controls different biological functions including pain and cough reflex. Mixed NOP/opioid receptor agonists elicit similar effects to strong opioids but with reduced side effects. In this work, 31 peptides with the general sequence [Tyr/Dmt1,Xaa5]N/OFQ(1-13)-NH2 were synthesized and pharmacologically characterized for their action at human recombinant NOP/opioid receptors. The best results in terms of NOP versus mu opioid receptor potency were obtained by substituting both Tyr1 and Thr5 at the N-terminal portion of N/OFQ(1-13)-NH2 with the noncanonical amino acid Dmt. [Dmt1,5]N/OFQ(1-13)-NH2 has been identified as the most potent dual NOP/mu receptor peptide agonist so far described. Experimental data have been complemented by in silico studies to shed light on the molecular mechanisms by which the peptide binds the active form of the mu receptor. Finally, the compound exerted antitussive effects in an in vivo model of cough.
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- 2021
38. Structure-Activity Relationship Studies on Oxazolo[3,4- a]pyrazine Derivatives Leading to the Discovery of a Novel Neuropeptide S Receptor Antagonist with Potent in Vivo Activity
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Girolamo Calò, Federica Ferrari, Chiara Ruzza, Giorgio Amendola, Sandro Cosconati, Rainer K Reinscheid, Erika Marzola, Chiara Sturaro, Tatiana Bernardi, Salvatore Pacifico, Claudio Trapella, Valentina Albanese, Anna Fantinati, Delia Preti, Martina Fabbri, Remo Guerrini, Albanese, V., Ruzza, C., Marzola, E., Bernardi, T., Fabbri, M., Fantinati, A., Trapella, C., Reinscheid, R. K., Ferrari, F., Sturaro, C., Calo, G., Amendola, G., Cosconati, S., Pacifico, S., Guerrini, R., and Preti, D.
- Subjects
Receptors, Neuropeptide ,Oxazoles ,Receptors, G-Protein-Coupled ,Structure-Activity Relationship ,Pharmacology ,01 natural sciences ,Article ,NO ,03 medical and health sciences ,G-Protein-Coupled ,In vivo ,Drug Discovery ,Neuropeptide S ,Receptors ,Structure–activity relationship ,Animals ,Humans ,Receptor ,Neuropeptide S receptor ,030304 developmental biology ,Mice, Knockout ,0303 health sciences ,Molecular Structure ,Chemistry ,Antagonist ,Ligand (biochemistry) ,In vitro ,0104 chemical sciences ,Molecular Docking Simulation ,010404 medicinal & biomolecular chemistry ,Neuropeptide ,HEK293 Cells ,Pyrazines ,Molecular Medicine ,Locomotion ,Protein Binding - Abstract
Neuropeptide S modulates important neurobiological functions including locomotion, anxiety, and drug abuse through interaction with its G protein-coupled receptor known as neuropeptide S receptor (NPSR). NPSR antagonists are potentially useful for the treatment of substance abuse disorders against which there is an urgent need for new effective therapeutic approaches. Potent NPSR antagonists in vitro have been discovered which, however, require further optimization of their in vivo pharmacological profile. This work describes a new series of NPSR antagonists of the oxazolo[3,4-a]pyrazine class. The guanidine derivative 16 exhibited nanomolar activity in vitro and 5-fold improved potency in vivo compared to SHA-68, a reference pharmacological tool in this field. Compound 16 can be considered a new tool for research studies on the translational potential of the NPSergic system. An in-depth molecular modeling investigation was also performed to gain new insights into the observed structure-activity relationships and provide an updated model of ligand/NPSR interactions.
- Published
- 2021
39. An Alternative Enzymatic Route to the Ergogenic Ketone Body Ester (R)-3-Hydroxybutyl (R)-3-Hydroxybutyrate
- Author
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Claudio Trapella, Marco Narducci, Pier Paolo Giovannini, Ferdinando Zaccone, Hugues Fournier, Valentina Venturi, and Anna Fantinati
- Subjects
0301 basic medicine ,analytical_chemistry ,asymmetric synthesis ,PE4_10 ,030204 cardiovascular system & hematology ,lcsh:Chemical technology ,Catalysis ,Kinetic resolution ,lcsh:Chemistry ,03 medical and health sciences ,chemistry.chemical_compound ,configuration inversion ,0302 clinical medicine ,Vinyl acetate ,lipase ,Organic chemistry ,lcsh:TP1-1185 ,kinetic resolution ,Physical and Theoretical Chemistry ,Lipase ,ketone body ester ,biology ,Chemistry ,Enantioselective synthesis ,Ambientale ,Transesterification ,biology.organism_classification ,PE5_17 ,030104 developmental biology ,lcsh:QD1-999 ,Yield (chemistry) ,biology.protein ,Candida antarctica ,Enantiomer ,Asymmetric synthesis ,Configuration inversion ,Ketone body ester - Abstract
The oral administration of (R)-3-hydroxybutyl-(R)-3-hydroxybutyrate, allows inducing a beneficial level of blood ketone bodies without the adverse effects due to the adhesion to a ketogenic diet. Several studies documented the therapeutic effectiveness of the (R)-3-hydroxybutyl (R)-3-hydroxybutyrate in treating neurodegenerative diseases as well as its boosting activity of athletic and cognitive performances during prolonged physical exercises. Further studies considering this ketone body ester for therapy of other pathologies are also underway. In the present work, we describe the synthesis of (R)-3-hydroxybutyl-(R)-3-hydroxybutyrate through the enantioselective transesterification of racemic ethyl 3-hydroxybutyrate with (R)-1,3-butanediol catalyzed by immobilized Candida antarctica lipase B (CAL-B). The enantiopure (R)-1,3-butanediol was in turn obtained from the kinetic resolution of the racemate by CAL-B catalyzed acetylation with vinyl acetate. The economy of the synthetic procedure has been improved by recycling the unreacted (S) enantiomers of the ethyl 3-hydroxybutyrate and 1,3-buatnediol after stereochemical inversion achieved by tosylation and SN2 with ammonium acetate. The overall procedure allows to incorporate up to 70% of the starting racemic reagents into the final product.
- Published
- 2020
40. Discovery of Novel Fetal Hemoglobin Inducers through Small Chemical Library Screening
- Author
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Elisabetta D'Aversa, Claudio Trapella, Shaiq Sultan, Remo Guerrini, Roberto Gambari, Delia Preti, Giulia Breveglieri, Lucia Carmela Cosenza, Cristina Zuccato, Salvatore Pacifico, and Monica Borgatti
- Subjects
0301 basic medicine ,Cell ,Drug Evaluation, Preclinical ,Gene Expression ,Biosensing Techniques ,beta-Globins ,Green fluorescent protein ,Chemical library ,lcsh:Chemistry ,chemistry.chemical_compound ,0302 clinical medicine ,hemic and lymphatic diseases ,Gene expression ,Drug Discovery ,gamma-Globins ,lcsh:QH301-705.5 ,Spectroscopy ,Chemistry ,Cell Differentiation ,General Medicine ,Flow Cytometry ,Computer Science Applications ,medicine.anatomical_structure ,Biochemistry ,030220 oncology & carcinogenesis ,β-thalassemia ,chemical screening ,congenital, hereditary, and neonatal diseases and abnormalities ,fetal hemoglobin ,Green Fluorescent Proteins ,compound library ,Anemia, Sickle Cell ,Catalysis ,Article ,Inorganic Chemistry ,Small Molecule Libraries ,03 medical and health sciences ,Fetal hemoglobin ,medicine ,Humans ,Physical and Theoretical Chemistry ,hemoglobinopathies ,Molecular Biology ,Gene ,Cell Proliferation ,Organic Chemistry ,beta-Thalassemia ,Promoter ,cellular biosensors ,Luminescent Proteins ,030104 developmental biology ,Gene Expression Regulation ,lcsh:Biology (General) ,lcsh:QD1-999 ,Cell culture ,Protein Biosynthesis ,sickle cell disease ,K562 Cells - Abstract
The screening of chemical libraries based on cellular biosensors is a useful approach to identify new hits for novel therapeutic targets involved in rare genetic pathologies, such as &beta, thalassemia and sickle cell disease. In particular, pharmacologically mediated stimulation of human &gamma, globin gene expression, and increase of fetal hemoglobin (HbF) production, have been suggested as potential therapeutic strategies for these hemoglobinopathies. In this article, we screened a small chemical library, constituted of 150 compounds, using the cellular biosensor K562.GR, carrying enhanced green fluorescence protein (EGFP) and red fluorescence protein (RFP) genes under the control of the human &gamma, globin and &beta, globin gene promoters, respectively. Then the identified compounds were analyzed as HbF inducers on primary cell cultures, obtained from &beta, thalassemia patients, confirming their activity as HbF inducers, and suggesting these molecules as lead compounds for further chemical and biological investigations.
- Published
- 2020
41. Pharmacological modulation of mitochondrial calcium uniporter controls lung inflammation in cystic fibrosis
- Author
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Giulio Cabrini, Anna Talarico, Ida De Fino, Alessandro Rimessi, Giacomo Rossi, Alice Rossi, Paolo Pinton, Serena Ranucci, Mariusz R. Wieckowski, Carla Ribeiro, Claudio Trapella, Alessandra Bragonzi, Lorenzo Carparelli, Cristina Cigana, and Chiara Pozzato
- Subjects
autophagy ,congenital, hereditary, and neonatal diseases and abnormalities ,Cystic Fibrosis ,inhibitor KB-R7943 ,molecular mechanisms ,chemistry.chemical_element ,receptors ,Inflammation ,Protein tyrosine phosphatase ,Calcium ,Mitochondrion ,medicine.disease_cause ,Cystic fibrosis ,NO ,resistance ,Mitochondrial Proteins ,03 medical and health sciences ,CA2+ ,0302 clinical medicine ,medicine ,Humans ,Health and Medicine ,Research Articles ,030304 developmental biology ,0303 health sciences ,Multidisciplinary ,Pseudomonas aeruginosa ,Endoplasmic reticulum ,Autophagy ,signals ,SciAdv r-articles ,Cell Biology ,Pneumonia ,respiratory system ,medicine.disease ,Cell biology ,respiratory tract diseases ,mitophagy ,chemistry ,NA+/CA2+ exchange ,NA+/CA2+ exchange, molecular mechanisms, inhibitor KB-R7943, autophagy, CA2+, mitophagy, receptors, signals, complex, resistance ,Calcium Channels ,medicine.symptom ,030217 neurology & neurosurgery ,complex ,Research Article - Abstract
Mitochondrial therapy offers an alternative strategy for attenuation of hyperinflammation in cystic fibrosis lung disease., Mitochondria physically associate with the endoplasmic reticulum to coordinate interorganelle calcium transfer and regulate fundamental cellular processes, including inflammation. Deregulated endoplasmic reticulum–mitochondria cross-talk can occur in cystic fibrosis, contributing to hyperinflammation and disease progression. We demonstrate that Pseudomonas aeruginosa infection increases endoplasmic reticulum–mitochondria associations in cystic fibrosis bronchial cells by stabilizing VAPB-PTPIP51 (vesicle-associated membrane protein–associated protein B–protein tyrosine phosphatase interacting protein 51) tethers, affecting autophagy. Impaired autophagy induced mitochondrial unfolding protein response and NLRP3 inflammasome activation, contributing to hyperinflammation. The mechanism by which VAPB-PTPIP51 tethers regulate autophagy in cystic fibrosis involves calcium transfer via mitochondrial calcium uniporter. Mitochondrial calcium uniporter inhibition rectified autophagy and alleviated the inflammatory response in vitro and in vivo, resulting in a valid therapeutic strategy for cystic fibrosis pulmonary disease.
- Published
- 2020
42. Methiopropamine and its acute behavioral effects in mice: is there a gray zone in new psychoactive substances users?
- Author
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Raffaella Arfè, Federica Foti, Sabrine Bilel, Francesco Botrè, Fabio De-Giorgio, Claudio Trapella, Margherita Neri, Cristian Camuto, Matteo Marti, Paolo Frisoni, and Micaela Tirri
- Subjects
Male ,Serotonin reuptake inhibitor ,Population ,Socio-culturale ,Stimulation ,Thiophenes ,Pharmacology ,Pathology and Forensic Medicine ,NO ,Methamphetamine ,chemistry.chemical_compound ,Workplace drug testing ,Mice ,Methiopropamine ,Novel psychoactive substances ,Heart rate ,medicine ,Animals ,education ,education.field_of_study ,Mice, Inbred ICR ,Psychotropic Drugs ,Pharmacodynamic ,Dose-Response Relationship, Drug ,business.industry ,Dopaminergic ,Behavioral effects ,Settore MED/43 - MEDICINA LEGALE ,chemistry ,Models, Animal ,Reuptake inhibitor ,business ,medicine.drug - Abstract
Methiopropamine is a structural analog of methamphetamine that is categorized as a novel psychoactive substance. It primarily acts as a norepinephrine–dopamine reuptake inhibitor and, secondarily, as a serotonin reuptake inhibitor. In humans, methiopropamine induces stimulation and alertness and increases focus and energy. However, significant side effects are reported, such as tachycardia, anxiety, panic attacks, perspiration, headache, and difficulty in breathing. To date, little data is available regarding its pharmacodynamic effects, thereby we aimed to investigate the acute in vivo effects induced by this drug on sensorimotor responses, body temperature, pain thresholds, motor activity, and cardiovascular and respiratory systems in CD-1 male mice. We selected a range of doses that correspond to the whole range of human reported use, in order to evaluate the threshold of adverse effects presentation. This study demonstrates that methiopropamine acts as a dopaminergic and noradrenergic stimulating drug and that the highest doses (10–30 mg/kg) impair the visual placing response, facilitate the acoustic and tactile response, induce hypothermia, increase mechanical and thermal analgesia, stimulate locomotor activity, induce motor stereotypies, and strongly affected cardiovascular and respiratory parameters, increasing heart rate, breath rate, and blood pressure but reducing oxygen saturation. On the contrary, lower doses do not show any of those effects. We hypothesize that there is a range of doses that do enhance performance but do not seem hazardous to users: this gap could induce the perception of safety and increase the abuser population.
- Published
- 2020
43. Review for 'Therapeutic potentials of NOP and MOP receptor coactivation for the treatment of pain and opioid abuse'
- Author
-
Claudio Trapella
- Subjects
business.industry ,NOP ,Opioid abuse ,Medicine ,business ,Receptor ,Bioinformatics ,Coactivation - Published
- 2020
44. Metabolic profile of the synthetic drug 4,4′-dimethylaminorex in urine by LC–MS-based techniques: selection of the most suitable markers of its intake
- Author
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Francesca Diamanti, Francesco Botrè, Cristian Camuto, Matteo Marti, Fabio De-Giorgio, Claudio Trapella, Claudia Chieffi, Xavier de la Torre, and Monica Mazzarino
- Subjects
Socio-culturale ,UHPLC–MS/MS ,Toxicology ,Tandem mass spectrometry ,01 natural sciences ,4,4′-Dimethylaminorex ,Anti-doping analysis ,CYP2D6 ,In vitro and in vivo metabolism studies ,Novel psychoactive substances (NPS) ,4′-Dimethylaminorex ,Pathology and Forensic Medicine ,Hydroxylation ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Liquid chromatography–mass spectrometry ,In vivo ,Enzymatic hydrolysis ,Chromatography ,biology ,010401 analytical chemistry ,Biochemistry (medical) ,Cytochrome P450 ,0104 chemical sciences ,Metabolic pathway ,chemistry ,Microsome ,biology.protein ,030217 neurology & neurosurgery - Abstract
Purpose In this study, the phase I and II metabolic pathways of 4,4′-dimethylaminorex were characterized to select the marker(s) of intake allowing the unequivocal identification of this novel psychoactive substance in urine samples. Methods The metabolic profile of 4,4′-dimethylaminorex was characterized using both in vitro and in vivo models. In detail, for the in vitro experiments, either pooled human liver microsomes or recombinant cytochrome P450 isoforms were selected, whereas the in vivo investigation was performed on male mice ICR (CD-1®). Sample preparation included enzymatic hydrolysis followed by liquid/liquid extraction. The instrumental analysis was performed by ultra-high-performance liquid chromatography coupled to either high- or low-resolution tandem mass spectrometry. Results Five metabolic products were isolated only for the cis-isomer: the phase I metabolic reactions included hydrolysis, carboxylation, hydroxylation, and carbonylation. CYP2D6 was the principal isoenzyme involved, and the incubation in the presence of different allelic variants showed significant alteration on the metabolic profile. Once formed, the phase I metabolites underwent extensive conjugation. Not only the most abundant compounds detected, but also those with the most extended window of detection, were the carboxylated and the hydroxylated metabolites. These analytes together with the parent compound were selected as the most suitable markers of intake. Conclusions Knowledge of the metabolic profiles of the new drugs is essential for their fast identification. Phase I and phase II metabolites of 4,4′-dimethylaminorex were identified and selected as markers of intake, to be considered as the most suitable analytical targets in forensic toxicology.
- Published
- 2020
45. Design of Nanosystems for the Delivery of Quorum Sensing Inhibitors : A Preliminary Study
- Author
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Rita Cortesi, Elisabetta Esposito, Supandeep Singh Hallan, Paolo Mariani, Claudio Trapella, Maddalena Sguizzato, Paolo Marchetti, Roberta Rizzo, and Daria Bortolotti
- Subjects
liposomes ,Biomaterialvetenskap ,nanotechnological systems ,Socio-culturale ,Pharmaceutical Science ,MTT test ,02 engineering and technology ,Article ,biofilm ,Analytical Chemistry ,lcsh:QD241-441 ,03 medical and health sciences ,chemistry.chemical_compound ,Drug Delivery Systems ,Pulmonary surfactant ,lcsh:Organic chemistry ,Drug Discovery ,Zeta potential ,LS7_3 ,Physical and Theoretical Chemistry ,030304 developmental biology ,0303 health sciences ,Liposome ,Bacteria ,Chemistry ,Organic Chemistry ,nanotechnological systems, liposomes,QS inhibitors, drug delivery, biofilm, MTT test ,Biofilm ,Quorum Sensing ,Ambientale ,021001 nanoscience & nanotechnology ,Combinatorial chemistry ,Anti-Bacterial Agents ,Quorum sensing ,Chemistry (miscellaneous) ,Biofilms ,Drug Design ,QS inhibitors ,Drug delivery ,drug delivery ,Biomaterials Science ,Nanoparticles ,Molecular Medicine ,Ammonium chloride ,0210 nano-technology ,Didecyldimethylammonium chloride - Abstract
Biofilm production is regulated by the Quorum Sensing system. Nowadays, Quorum Sensing represents an appealing target to design new compounds to increase antibiotics effects and avoid development of antibiotics multiresistance. In this research the use of liposomes to target two novel synthetic biofilm inhibitors is presented, focusing on a preformulation study to select a liposome composition for in vitro test. Five different liposome (LP) formulations, composed of phosphatidyl choline, cholesterol and charged surfactant (2:1:1, molar ratio) have been prepared by direct hydration and extrusion. As charged surfactants dicetyl phosphate didecyldimethylammonium chloride, di isobutyl phenoxy ethyl dimethyl benzyl ammonium chloride and stearylamine (SA) and have been used. Liposome charge, size and morphology were investigated by zeta potential, photon correlation spectroscopy, small angle x-ray spectroscopy and electron microscopy. LP-SA was selected for the loading of biofilm inhibitors and subjected to high performance liquid chromatography for entrapment capacity evaluation. LP-SA loaded inhibitors showed a higher diameter (223.6 nm) as compared to unloaded ones (205.7 nm) and a dose-dependent anti-biofilm effect mainly after 48 h of treatment, while free biofilm inhibitors loose activity. In conclusion, our data supported the use of liposomes as a strategy to enhance biofilm inhibitors effect.
- Published
- 2020
46. Discovery of Novel 1,3,8-Triazaspiro[4.5]decane Derivatives That Target the c Subunit of F1/FO-Adenosine Triphosphate (ATP) Synthase for the Treatment of Reperfusion Damage in Myocardial Infarction
- Author
-
Natascia Caroccia, Sonia Missiroli, Mariusz R. Wieckowski, Claudia Morganti, Carlotta Giorgi, Claudio Trapella, Salvatore Pacifico, Delia Preti, Paolo Pinton, Anna Fantinati, Giampaolo Morciano, Giorgio Aquila, Gaia Pedriali, Gianluca Campo, Anna Talarico, Roberto Ferrari, Paola Rizzo, and Massimo Bonora
- Subjects
0301 basic medicine ,injury ,Mitochondrion ,Pharmacology ,NO ,dimers ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,inhibitors ,Drug Discovery ,Structure–activity relationship ,Heart metabolism ,Mitochondrial permeability transition ,ATP synthase ,biology ,MPTP ,apoptosis ,cyclosporine-a ,030104 developmental biology ,chemistry ,Mitochondrial permeability transition pore ,membranes ,Apoptosis ,biology.protein ,Molecular Medicine ,living cells ,pore ,Adenosine triphosphate ,ring ,030217 neurology & neurosurgery - Abstract
Recent cardiology research studies have reported the role, function, and structure of the mitochondrial permeability transition pore (mPTP) and have shown that its opening plays a key role in the progression of myocardial cell death secondary to reperfusion. In this manuscript, we validated a new pharmacological approach as an adjunct to reperfusion in myocardial infarction (MI) treatment and describe the discovery, optimization, and structure–activity relationship (SAR) studies of the first small-molecule mPTP opening inhibitors based on a 1,3,8-triazaspiro[4.5]decane scaffold that targets the c subunit of the F1/FO-ATP synthase complex. We identified three potential compounds with good mPTP inhibitory activity and beneficial effects in a model of MI, including a decreased apoptotic rate in the whole heart and overall improvement of cardiac function upon administration during reperfusion. The selected compounds did not show off-target effects at the cellular and mitochondrial levels. Moreover, the compou...
- Published
- 2018
47. 1,4-Dithiane-2,5-diol: An Attractive Platform for the Synthesis of Sulfur-Containing Functionalized Heterocycles
- Author
-
Anna Fantinati, Claudio Trapella, and Francesco Zamberlan
- Subjects
010405 organic chemistry ,Organic Chemistry ,Synthon ,Diol ,chemistry.chemical_element ,010402 general chemistry ,01 natural sciences ,Sulfur ,0104 chemical sciences ,chemistry.chemical_compound ,chemistry ,Aldol reaction ,Nucleophile ,Organic chemistry ,Organic synthesis ,Physical and Theoretical Chemistry ,Thiazole ,Dithiane - Abstract
This microreview highlights the utility of 1,4? dithiane?2,5?diol 1 as a source for the in situ generation of 2?mercaptoacetaldehyde 2, a versatile two?carbon synthon featuring both electrophilic and nucleophilic reaction centers widely utilized as an attractive platform for the preparation of sulfur?containing molecules. We discussed the involved chemistry, mainly focusing on its applications to the construction of sulfur?containing heterocyclic compounds including the thiophene and 1,3?thiazole families and other different sulfur?nitrogen and sulfur?oxygen heterocycles which continue to be a pillar of organic synthesis as a result of their broad application in organic and medicinal chemistry.
- Published
- 2018
48. Glyceric Prodrug of Ursodeoxycholic Acid (UDCA): Novozym 435-Catalyzed Synthesis of UDCA-Monoglyceride
- Author
-
Claudio Trapella, Federico Zappaterra, Bruno Semeraro, Daniela Summa, Stefania Costa, Virginia Cristofori, and Elena Tamburini
- Subjects
Glycerol ,Magnetic Resonance Spectroscopy ,ursodeoxycholic acid ,monoglyceride ,esterification ,CALB ,prodrug ,medicine.drug_class ,Pharmaceutical Science ,Pharmacology ,Catalysis ,Mass Spectrometry ,Article ,Cholangiocyte ,NO ,Analytical Chemistry ,Fungal Proteins ,chemistry.chemical_compound ,QD241-441 ,Primary biliary cirrhosis ,Enzyme Stability ,Drug Discovery ,medicine ,Prodrugs ,Physical and Theoretical Chemistry ,Chromatography, High Pressure Liquid ,Bile acid ,biology ,Cholesterol ,Basidiomycota ,Organic Chemistry ,Temperature ,Prodrug ,Enzymes, Immobilized ,medicine.disease ,biology.organism_classification ,Ursodeoxycholic acid ,Bioavailability ,Solubility ,chemistry ,Chemistry (miscellaneous) ,Solvents ,Monoglycerides ,Molecular Medicine ,Candida antarctica ,medicine.drug - Abstract
Bile acids (BAs) are a family of steroids synthesized from cholesterol in the liver. Among bile acids, ursodeoxycholic acid (UDCA) is the drug of choice for treating primary biliary cirrhosis and dissolving cholesterol gallstones. The clinical effectiveness of UDCA includes its choleretic activity, the capability to inhibit hydrophobic bile acid absorption by the intestine under cholestatic conditions, reducing cholangiocyte injury, stimulation of impaired biliary output, and inhibition of hepatocyte apoptosis. Despite its clinical effectiveness, UDCA is poorly soluble in the gastro-duodeno-jejunal contents, and pharmacological doses of UDCA are not readily soluble in the stomach and intestine, resulting in incomplete absorption. Indeed, the solubility of 20 mg/L greatly limits the bioavailability of UDCA. Since the bioavailability of drug products plays a critical role in the design of oral administration dosages, we investigated the enzymatic esterification of UDCA as a strategy of hydrophilization. Therefore, we decided to enzymatically synthesize a glyceric ester of UDCA bile acid to produce a more water-soluble molecule. The esterification reactions between UDCA and glycerol were performed with an immobilized lipase B from Candida antarctica (Novozym 435) in solvent-free and solvent-assisted systems. The characterization of the UDCA-monoglyceride, enzymatically synthesized, has been performed by 1H-NMR, 13C-NMR, COSY, HSQC, HMBC, IR, and MS spectroscopy.
- Published
- 2021
49. Antinociceptive action of NOP and opioid receptor agonists in the mouse orofacial formalin test
- Author
-
Girolamo Calo, Claudio Trapella, Anna Rizzi, Chiara Ruzza, and Sara Bianco
- Subjects
Male ,0301 basic medicine ,Agonist ,Indoles ,Physiology ,medicine.drug_class ,NOP ,Socio-culturale ,Pain ,Orofacial formalin test ,Cebranopadol ,Pharmacology ,Biochemistry ,Nociceptin Receptor ,Mixed NOP/opioid agonists ,Mice ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,Endocrinology ,Opioid receptor ,Animals, Outbred Strains ,medicine ,Animals ,Spiro Compounds ,Receptor ,Pain Measurement ,Mice, Knockout ,Isobolographic analysis ,Analgesics ,Morphine ,Chemistry ,Imidazoles ,Nociceptin receptor ,030104 developmental biology ,Opioid ,Rotarod Performance Test ,Receptors, Opioid ,030217 neurology & neurosurgery ,medicine.drug - Abstract
Nociceptin/orphanin FQ (N/OFQ) modulates several biological functions, including pain transmission via selective activation of a specific receptor named NOP. The aim of this study was the investigation of the antinociceptive properties of NOP agonists and their interaction with opioids in the trigeminal territory. The orofacial formalin (OFF) test in mice was used to investigate the antinociceptive potential associated to the activation of NOP and opioid receptors. Mice subjected to OFF test displayed the typical biphasic nociceptive response and sensitivity to opioid and NSAID drugs. Mice knockout for the NOP gene displayed a robust pronociceptive phenotype. The NOP selective agonist Ro 65-6570 (0.1-1mgkg-1) and morphine (0.1-10mgkg-1) elicited dose dependent antinociceptive effects in the OFF with the alkaloid showing larger effects; the isobologram analysis of their actions demonstrated an additive type of interaction. The mixed NOP/opioid receptor agonist cebranopadol elicited potent (0.01-0.1mgkg-1) and robust antinociceptive effects. In the investigated dose range, all drugs did not modify the motor performance of the mice in the rotarod test. Collectively the results of this study demonstrated that selective NOP agonists and particularly mixed NOP/opioid agonists are worthy of development as innovative drugs to treat painful conditions of the trigeminal territory.
- Published
- 2017
50. Author Correction: HelixComplex snail mucus exhibits pro-survival, proliferative and pro-migration effects on mammalian fibroblasts
- Author
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Stefania Gallo, Claudio Trapella, Roberta Rizzo, Rebecca Voltan, Fabio Casciano, Giorgio Zauli, Daria Bortolotti, Andrea Alogna, and Paola Secchiero
- Subjects
Multidisciplinary ,biology ,biology.animal ,lcsh:R ,lcsh:Medicine ,lcsh:Q ,Snail ,lcsh:Science ,Mucus ,Cell biology - Abstract
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
- Published
- 2020
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