Gilberto Spadoni

Publications (47)155.6 Total impact

• Article: Homology models of melatonin receptors: challenges and recent advances.

  Daniele Pala, Alessio Lodola, Annalida Bedini, Gilberto Spadoni, Silvia Rivara
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  ABSTRACT: Melatonin exerts many of its actions through the activation of two G protein-coupled receptors (GPCRs), named MT1 and MT2. So far, a number of different MT1 and MT2 receptor homology models, built either from the prototypic structure of rhodopsin or from recently solved X-ray structures of druggable GPCRs, have been proposed. These receptor models differ in the binding modes hypothesized for melatonin and melatonergic ligands, with distinct patterns of ligand-receptor interactions and putative bioactive conformations of ligands. The receptor models will be described, and they will be discussed in light of the available information from mutagenesis experiments and ligand-based pharmacophore models. The ability of these ligand-receptor complexes to rationalize structure-activity relationships of known series of melatonergic compounds will be commented upon.
  International Journal of Molecular Sciences 01/2013; 14(4):8093-121. · 2.60 Impact Factor
• Article: MT(1) -Selective Melatonin Receptor Ligands: Synthesis, Pharmacological Evaluation, and Molecular Dynamics Investigation of N-{[(3-O-Substituted)anilino]alkyl}amides.

  Silvia Rivara, Daniele Pala, Alessio Lodola, Marco Mor, Valeria Lucini, Silvana Dugnani, Francesco Scaglione, Annalida Bedini, Simone Lucarini, Giorgio Tarzia, Gilberto Spadoni
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  ABSTRACT: The design of compounds selective for the MT(1) melatonin receptor is still a challenging task owing to the limited knowledge of the structural features conferring selectivity for the MT(1) subtype, and only few selective compounds have been reported so far. N-(Anilinoalkyl)amides are a versatile class of melatonin receptor ligands that include nonselective MT(1) /MT(2) agonists and MT(2) -selective antagonists. We synthesized a new series of N-(anilinoalkyl)amides bearing 3-arylalkyloxy or 3-alkyloxy substituents at the aniline ring, looking for new potent and MT(1) -selective ligands. To evaluate the effect of substituent size and shape on binding affinity and intrinsic activity, both flexible and conformationally constrained derivatives were prepared. The phenylbutyloxy substituent gave the best result, providing the partial agonist 4 a, which was endowed with high MT(1) binding affinity (pK(i) =8.93) and 78-fold selectivity for the MT(1) receptor. To investigate the molecular basis for agonist recognition, and to explain the role of the 3-arylalkyloxy substituent, we built a homology model of the MT(1) receptor based on the β(2) adrenergic receptor crystal structure in its activated state. A binding mode for MT(1) agonists is proposed, as well as a hypothesis regarding the receptor structural features responsible for MT(1) selectivity of compounds with lipophilic arylalkyloxy substituents.
  ChemMedChem 08/2012; · 3.15 Impact Factor
• Source

  Available from: Gabriella Gobbi

  Article: Anxiolytic effects of the melatonin MT(2) receptor partial agonist UCM765: Comparison with melatonin and diazepam.

  Rafael Ochoa-Sanchez, Quentin Rainer, Stefano Comai, Gilberto Spadoni, Annalida Bedini, Silvia Rivara, Franco Fraschini, Marco Mor, Giorgio Tarzia, Gabriella Gobbi
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  ABSTRACT: Melatonin (MLT) is a neurohormone known to be involved in the regulation of anxiety. Most of the physiological actions of MLT in the brain are mediated by two high-affinity G-protein-coupled receptors, denoted MT(1) and MT(2). However, the particular role of these receptors in anxiety remains to be defined. Here we used a novel MT(2)-selective partial agonist, UCM765 to evaluate the involvement of MT(2) receptors in anxiety. Adult male rats were acutely injected with UCM765 (5-10-20mg/kg), MLT (20mg/kg) or diazepam (DZ, 1mg/kg). Anxiety-related behaviors were assessed in the elevated plus maze test (EPMT), novelty suppressed feeding test (NSFT) and open field test (OFT). UCM765 at the dose of 10mg/kg showed anxiolytic-like properties by increasing the time spent in the open arm of the EPMT, and by reducing the latency to eat in a novel environment in the NSFT. In the EPMT, animals treated with UCM765 (10mg/kg) or MLT (20mg/kg) spent more time in the open arms compared to vehicle-treated animals, but to a lesser extent compared to DZ (1mg/kg). In the NSFT, all treatments similarly decreased the latency to eat in a novel environment compared to vehicle. UCM765 and MLT did not affect the total time and the number of entries into the central area of the OFT, but unlike DZ, did not impair locomotion. The anxiolytic effects of UCM765 and MLT in the EPMT and the NSFT were blocked using a pre-treatment with the MT(1)/MT(2) antagonist luzindole (10mg/kg) or the MT(2) antagonist 4P-PDOT (10mg/kg). These results demonstrated, for the first time, the anxiolytic properties of UCM765 and suggest that MT(2)-receptors may be considered a novel target for the development of anxiolytic drugs.
  Progress in Neuro-Psychopharmacology and Biological Psychiatry 07/2012; 39(2):318-25. · 3.25 Impact Factor
• Article: Synthesis of tryptamine derivatives via a direct, one-pot reductive alkylation of indoles.

  Marika Righi, Francesca Topi, Silvia Bartolucci, Annalida Bedini, Giovanni Piersanti, Gilberto Spadoni
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  ABSTRACT: An efficient, one-pot reductive alkylation of indoles with N-protected aminoethyl acetals in the presence of TES/TFA is reported. It represents the first general method for the direct synthesis of tryptamine derivatives from indoles and nitrogen-functionalized acetals. This convergent and versatile approach employs safe and inexpensive reagents, proceeds under mild conditions, and tolerates several functional groups. The new procedure was efficiently applied to a gram-scale synthesis of both luzindole, a reference MT2-selective melatonin receptor antagonist, and melatonin.
  The Journal of Organic Chemistry 06/2012; 77(14):6351-7. · 4.45 Impact Factor
• Source

  Available from: Gabriella Gobbi

  Article: Promotion of non-rapid eye movement sleep and activation of reticular thalamic neurons by a novel MT2 melatonin receptor ligand.

  Rafael Ochoa-Sanchez, Stefano Comai, Baptiste Lacoste, Francis Rodriguez Bambico, Sergio Dominguez-Lopez, Gilberto Spadoni, Silvia Rivara, Annalida Bedini, Debora Angeloni, Franco Fraschini, Marco Mor, Giorgio Tarzia, Laurent Descarries, Gabriella Gobbi
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  ABSTRACT: Melatonin activates two brain G-protein coupled receptors, MT(1) and MT(2), whose differential roles in the sleep-wake cycle remain to be defined. The novel MT(2) receptor partial agonist, N-{2-[(3-methoxyphenyl) phenylamino] ethyl} acetamide (UCM765), is here shown to selectively promote non-rapid eye movement sleep (NREMS) in rats and mice. The enhancement of NREMS by UCM765 is nullified by the pharmacological blockade or genetic deletion of MT(2) receptors. MT(2), but not MT(1), knock-out mice show a decrease in NREMS compared to the wild strain. Immunohistochemical labeling reveals that MT(2) receptors are localized in sleep-related brain regions, and notably the reticular thalamic nucleus (Rt). Microinfusion of UCM765 in the Rt promotes NREMS, and its systemic administration induces an increase in firing and rhythmic burst activity of Rt neurons, which is blocked by the MT(2) antagonist 4-phenyl-2-propionamidotetralin. Since developing hypnotics that increase NREMS without altering sleep architecture remains a medical challenge, MT(2) receptors may represent a novel target for the treatment of sleep disorders.
  Journal of Neuroscience 12/2011; 31(50):18439-52. · 7.11 Impact Factor
• Article: Synthesis and configuration determination of all enantiopure stereoisomers of the melatonin receptor ligand 4-phenyl-2-propionamidotetralin using an expedient optical resolution of 4-phenyl-2-tetralone.

  Simone Lucarini, Silvia Bartolucci, Annalida Bedini, Giuseppe Gatti, Pierfrancesco Orlando, Giovanni Piersanti, Gilberto Spadoni
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  ABSTRACT: An efficient and practical approach for the synthesis of all four stereoisomers of the MT(2) melatonin receptor ligand 4-phenyl-2-propionamidotetralin (4-P-PDOT), each in enantiomerically pure form (ee > 99.9%), was developed. The strategy involved an optical resolution procedure of the key precursor (±)-4-phenyl-2-tetralone with the unusual resolving agent (S)-mandelamide, through the formation of four dihydronaphtalene-spiro-oxazolidin-4-one diastereomers. Interestingly, NMR experimental observations in combination with geometric calculations, provided unambiguous configuration assignments of all stereocenters of the key spiro stereoisomers. Cleavage of each single spiro diastereomer under acidic conditions gave enantiopure (R)- or (S)-4-phenyl-2-tetralone, which were then converted to each 4-P-PDOT single enantiomer by using stereoselective reactions.
  Organic & Biomolecular Chemistry 11/2011; 10(2):305-13. · 3.70 Impact Factor
• Article: Toward the definition of stereochemical requirements for MT2-selective antagonists and partial agonists by studying 4-phenyl-2-propionamidotetralin derivatives.

  Annalida Bedini, Simone Lucarini, Gilberto Spadoni, Giorgio Tarzia, Francesco Scaglione, Silvana Dugnani, Marilou Pannacci, Valeria Lucini, Caterina Carmi, Daniele Pala, Silvia Rivara, Marco Mor
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  ABSTRACT: New derivatives of 4-phenyl-2-propionamidotetralin (4-P-PDOT) were prepared and tested on cloned MT1 and MT2 receptors, with the purpose of merging previously reported pharmacophores for nonselective agonists and for MT2-selective antagonists. A 8-methoxy group increases binding affinity of both (±)-cis- and (±)-trans-4-P-PDOT, and it can be bioisosterically replaced by a bromine. Conformational analysis of 8-methoxy-4-P-PDOT by molecular dynamics, supported by NMR data, revealed an energetically favored conformation for the (2S,4S)-cis isomer and a less favorable conformation for the (2R,4S)-trans one, fulfilling the requirements of a pharmacophore model for nonselective melatonin receptor agonists. A new superposition model, including features characteristic of MT2-selective antagonists, suggests that MT1/MT2 agonists and MT2 antagonists can share the same arrangement for their pharmacophoric elements. The model correctly predicted the eutomers of (±)-cis- and (±)-trans-4-P-PDOT. The model was validated by preparing three dihydronaphthalene derivatives, either able or not able to reproduce the putative active conformation of 4-P-PDOT.
  Journal of Medicinal Chemistry 11/2011; 54(24):8362-72. · 4.80 Impact Factor
• Article: Description of the constitutive activity of cloned human melatonin receptors hMT1 and hMT2 and discovery of inverse agonists

  Séverine Devavry, Céline Legros, Chantal Brasseur, Philippe Delagrange, Gilberto Spadoni, William Cohen, Benoît Malpaux, Jean A. Boutin, Olivier Nosjean
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  ABSTRACT:   Melatonin receptors have been described to activate different G protein–dependent signaling pathways, both in laboratory, heterologous, cellular models and in physiological conditions. Furthermore, the constitutive activity of G protein–coupled receptors has been shown to be key in physiological and pathological conditions. In the case of melatonin receptors, information is rather scare and concerns only MT1 receptors. In the present report, we show that the G protein–coupled melatonin receptors do have a constitutive, nonmelatonin-induced signaling activity using two cellular models of different origins, the Chinese hamster ovary cell line and Neuro2A, a neuroblastoma cell line. Furthermore, we show that this constitutive activity involves mainly Gi proteins, which is consistent with the common knowledge on the melatonin receptors. Importantly, we also describe, for the first time, inverse agonist properties for melatonin ligands. Although it is clear than more in-depth, biochemistry-based studies will be required to better understand by which pathway(s) the constitutively active melatonin receptors transfer melatonin information into intracellular biochemical events; our data open interesting perspectives for understanding the importance of the constitutive activity of melatonin receptors in physiological conditions.
  Journal of Pineal Research 10/2011; · 5.79 Impact Factor
• Article: Bivalent ligand approach on N-{2-[(3-methoxyphenyl)methylamino]ethyl}acetamide: synthesis, binding affinity and intrinsic activity for MT(1) and MT(2) melatonin receptors.

  Gilberto Spadoni, Annalida Bedini, Pierfrancesco Orlando, Simone Lucarini, Giorgio Tarzia, Marco Mor, Silvia Rivara, Valeria Lucini, Marilou Pannacci, Francesco Scaglione
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  ABSTRACT: We report the synthesis, binding properties and intrinsic activity at MT(1) and MT(2) melatonin receptors of new dimeric melatonin receptor ligands in which two units of the monomeric agonist N-{2-[(3-methoxyphenyl)methylamino]ethyl}acetamide (1) are linked together through different anchor points. Dimerization of compound 1 through the methoxy substituent leads to a substantial improvement in selectivity for the MT(1) receptor, and to a partial agonist behavior. Compound 3a, with a trimethylene linker, was the most selective for the MT(1) subtype (112-fold selectivity) and compound 3d, characterized by a hexamethylene spacer, had the highest MT(1) binding affinity (pK(iMT1)=8.47) and 54-fold MT(1)-selectivity. Dimerization through the aniline nitrogen of 1 abolished MT(1) selectivity, leading to compounds with either a full agonist or an antagonist behavior depending on the nature of the linker.
  Bioorganic & medicinal chemistry 08/2011; 19(16):4910-6. · 2.82 Impact Factor
• Article: ST1936 stimulates cAMP, Ca2+, ERK1/2 and Fyn kinase through a full activation of cloned human 5-HT6 receptors.

  Teresa Riccioni, Fabio Bordi, Patrizia Minetti, Gilberto Spadoni, Hyung-Mun Yun, Bo-Hye Im, Giorgio Tarzia, Hyewhon Rhim, Franco Borsini
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  ABSTRACT: 5-HT(6) receptor is one of the most recently cloned serotonin receptors, and it might play important roles in Alzheimer's disease, depression, and learning and memory disorders. Availability of only very few 5-HT(6) receptor agonists, however, does not allow examining their contribution in psychopharmacological processes. Therefore, a new 5-HT(6) receptor agonist, ST1936, was synthesized. ST1936 binds to human 5-HT(6) receptors with good affinity (K(i)=28.8 nM). ST1936 also exhibited some moderate binding affinity for 5HT(2B), 5HT(1A), 5HT(7) receptors and adrenergic α receptors. ST1936 behaved as a full 5-HT(6) agonist on cloned cells and was able to increase Ca(2+) concentration, phosphorylation of Fyn kinase, and regulate the activation of ERK1/2 that is a downstream target of Fyn kinase. These effects were completely antagonized by two 5-HT(6) receptor antagonists, SB271046 and SB258585. The other 5-HT(6) receptor agonist, WAY181187 also increased Fyn kinase activity. These results suggest that both ST1936 and WAY181187 mediate 5-HT(6) receptor-dependent signal pathways, such as cAMP, Fyn and ERK1/2 kinase, as specific agonists.
  European journal of pharmacology 07/2011; 661(1-3):8-14. · 2.59 Impact Factor
• Article: Direct, one-pot reductive alkylation of anilines with functionalized acetals mediated by triethylsilane and TFA. Straightforward route for unsymmetrically substituted ethylenediamine.

  Marika Righi, Annalida Bedini, Giovanni Piersanti, Federica Romagnoli, Gilberto Spadoni
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  ABSTRACT: A new, robust, and reliable method has been developed for the selective reductive N-alkylation of primary and secondary aromatic amines with some functionalized acetals using TFA/Et(3)SiH as a reagent combination. A variety of unsymmetrically substituted ethylenediamines can be synthesized in a one-pot procedure in excellent yields at room temperature. This new procedure offers significant advantages over previous synthetic approaches, including brevity, mild reaction conditions, excellent yields, and high functional group tolerance.
  The Journal of Organic Chemistry 01/2011; 76(2):704-7. · 4.45 Impact Factor
• Article: Melatonin receptor agonists: new options for insomnia and depression treatment.

  Gilberto Spadoni, Annalida Bedini, Silvia Rivara, Marco Mor
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  ABSTRACT: The circadian nature of melatonin (MLT) secretion, coupled with the localization of MLT receptors to the suprachiasmatic nucleus, has led to numerous studies of the role of MLT in modulation of the sleep-wake cycle and circadian rhythms in humans. Although much more needs to be understood about the various functions exerted by MLT and its mechanisms of action, three therapeutic agents (ramelteon, prolonged-release MLT, and agomelatine) are already in use, and MLT receptor agonists are now appearing as new promising treatment options for sleep and circadian-rhythm related disorders. In this review, emphasis has been placed on medicinal chemistry strategies leading to MLT receptor agonists, and on the evidence supporting therapeutic efficacy of compounds undergoing clinical evaluation. A wide range of clinical trials demonstrated that ramelteon, prolonged-release MLT and tasimelteon have sleep-promoting effects, providing an important treatment option for insomnia and transient insomnia, even if the improvements of sleep maintenance appear moderate. Well-documented effects of agomelatine suggest that this MLT agonist offers an attractive alternative for the treatment of depression, combining efficacy with a favorable side effect profile. Despite a large number of high affinity nonselective MLT receptor agonists, only limited data on MT₁ or MT₂ subtype-selective compounds are available up to now. Administration of the MT₂-selective agonist IIK7 to rats has proved to decrease NREM sleep onset latency, suggesting that MT₂ receptor subtype is involved in the acute sleep-promoting action of MLT; rigorous clinical studies are needed to demonstrate this hypothesis. Further clinical candidates based on selective activation of MT₁ or MT₂ receptors are expected in coming years.
  CNS Neuroscience & Therapeutics 10/2010; 17(6):733-41. · 4.44 Impact Factor
• Article: A novel one-pot approach of hexahydropyrrolo[2,3-b]indole nucleus by a cascade addition/cyclization strategy: synthesis of (+/-)-esermethole.

  Simone Lucarini, Francesca Bartoccini, Flavia Battistoni, Giuseppe Diamantini, Giovanni Piersanti, Marika Righi, Gilberto Spadoni
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  ABSTRACT: A practical and efficient synthesis of 3-substituted hexahydropyrrolo[2,3-b]indole is described. The addition/cyclization of 3-substituted indoles with alpha,beta-dehydroamino esters in the presence of a Lewis acid provides hexahydropyrrolo[2,3-b]indole adducts in good yields and stereoselectivities. This approach has been applied to the concise synthesis of esermethole employing an appropriately substituted indole and an N-acyl dehydroamino ester.
  Organic Letters 09/2010; 12(17):3844-7. · 5.86 Impact Factor
• Article: Recent advances in the development of melatonin MT(1) and MT(2) receptor agonists.

  Marco Mor, Silvia Rivara, Daniele Pala, Annalida Bedini, Gilberto Spadoni, Giorgio Tarzia
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  ABSTRACT: Increasing clinical evidences suggest that melatonin receptor agonists can represent a novel therapeutic approach for the treatment of sleep disturbances and depression. A variety of studies also revealed a role of melatonin and its receptors in different patho-physiological conditions. Due to the multiple effects of this hormone, the design of new agents able to interact selectively with melatonin receptors has become an area of great interest during the last decade. An extensive inspection of patents and scientific literature about MT(1) and MT(2) melatonin receptor agonists reported from 1999 to early 2010. A comprehensive review of structures recently claimed as melatonin receptor agonists and a broad overview of structure-activity relationships for these ligands. After 5 decades of research, the field of melatonin receptor agonists comprises a variety of chemical entities, belonging to structurally different classes. Patents filed since 1999 claim new melatonin receptor agonists, characterized either by improved pharmacokinetic or pharmacodynamic properties, compared to those of melatonin receptor agonists already approved for clinical uses. The results of preclinical studies on animal models show that melatonin receptor agonists can be considered promising agents for the treatment of CNS-related pathologies.
  Expert Opinion on Therapeutic Patents 08/2010; 20(8):1059-77. · 3.57 Impact Factor
• Article: Recent advances in the development of melatonin MT1 and MT2 receptor agonists

  Marco Mor, Silvia Rivara, Daniele Pala, Annalida Bedini, Gilberto Spadoni, Giorgio Tarzia
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  ABSTRACT: Importance of the field: Increasing clinical evidences suggest that melatonin receptor agonists can represent a novel therapeutic approach for the treatment of sleep disturbances and depression. A variety of studies also revealed a role of melatonin and its receptors in different patho-physiological conditions. Due to the multiple effects of this hormone, the design of new agents able to interact selectively with melatonin receptors has become an area of great interest during the last decade. Areas covered in this review: An extensive inspection of patents and scientific literature about MT1 and MT2 melatonin receptor agonists reported from 1999 to early 2010. What the reader will gain: A comprehensive review of structures recently claimed as melatonin receptor agonists and a broad overview of structure–activity relationships for these ligands. Take home message: After 5 decades of research, the field of melatonin receptor agonists comprises a variety of chemical entities, belonging to structurally different classes. Patents filed since 1999 claim new melatonin receptor agonists, characterized either by improved pharmacokinetic or pharmacodynamic properties, compared to those of melatonin receptor agonists already approved for clinical uses. The results of preclinical studies on animal models show that melatonin receptor agonists can be considered promising agents for the treatment of CNS-related pathologies.
  07/2010; 20(8):1059-1077.
• Article: Diastereo- and enantioselective hydrogenation of a challenging enamide derived from 4-phenyl-2-tetralone: an appealing shortcut towards enantiopure cis-2-aminotetraline derivatives.

  Simone Lucarini, Matteo Alessi, Annalida Bedini, Giorgia Giorgini, Giovanni Piersanti, Gilberto Spadoni
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  ABSTRACT: A clean, efficient, and diasteroselective (dr >95%) catalytic hydrogenation of the enamide N-(4-phenyl-3,4-dihydronaphthalen-2-yl)propionamide (2 a) using palladium on carbon is performed. This procedure provides the melatonin receptor ligand (+/-)-cis-4-phenyl-2-propionamidotetralin (cis-4-P-PDOT, 1 a) and its 8-methoxy analog. Furthermore, Rh and Ru catalyzed homogeneous asymmetric hydrogenation of the challenging racemic endocyclic enamide 2 a with several chiral phosphine ligands is studied. The best results, in terms of enantioselectivity, for both diastereomers are obtained when chiral Rh-Josiphos is used as the catalyst.
  Chemistry - An Asian Journal 03/2010; 5(3):550-4. · 4.50 Impact Factor
• Article: N-(Anilinoethyl)amides: design and synthesis of metabolically stable, selective melatonin receptor ligands.

  Silvia Rivara, Federica Vacondio, Alessandro Fioni, Claudia Silva, Caterina Carmi, Marco Mor, Valeria Lucini, Marilou Pannacci, Alessia Caronno, Francesco Scaglione, Gabriella Gobbi, Gilberto Spadoni, Annalida Bedini, Pierfrancesco Orlando, Simone Lucarini, Giorgio Tarzia
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  ABSTRACT: The class of N-(anilinoethyl)amides includes melatonin receptor ligands with varied subtype selectivity and intrinsic activity. One of these ligands, the MT(2)-selective partial agonist UCM765 (N-{2-[(3-methoxyphenyl)phenylamino]ethyl}acetamide), had evidenced hypnotic effects in rodents at doses > or =40 mg kg(-1) (s.c.), in spite of its sub-nanomolar affinity for human melatonin receptors. Supposing that its low in vivo potency could be due, at least in part, to metabolic liability in rat liver, UCM765 was incubated with rat liver S9 fraction and rat, mouse, or human microsomes, and the major metabolites were identified by LC-MS, synthesized, and in vitro tested for their affinity toward MT(1) and MT(2) receptors. The obtained information was exploited to design novel analogues of UCM765 that are more resistant to in vitro oxidative degradation, while maintaining a similar binding profile. The analogue UCM924 (N-{2-[(3-bromophenyl)-(4-fluorophenyl)amino]ethyl}acetamide) displayed a binding profile similar to that of UCM765 on cloned human receptors (MT(2)-selective partial agonist) and a significantly longer half-life in the presence of rat liver S9 fraction.
  ChemMedChem 09/2009; 4(10):1746-55. · 3.15 Impact Factor
• Article: 4,5‐Dihydroisoxazole and 4,5‐dihydro‐1,2,4‐oxadiazole derivatives from cycloaddition reactions of nitrile oxides to alkyl N‐(diphenylmethylene)‐α,β‐dehydroamino acids

  Cesarino Balsamini, Gilberto Spadoni, Annalida Bedini, Giorgio Tarzia, Maurizio Lanfranchi, Maria Angela Pellinghelli
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  ABSTRACT: The alkyl N-(diphenylmethylene)-α,β-dehydroamino acids 1 have been submitted to 1,3-dipolar cycloadditions with nitrile oxides. The reactivity of these compounds depends on the type and on the stereochemistry of the β-substituents. With the unsubstituted terms 1a,b the reaction occurs on the C,C double bond, providing a good method for the synthesis of the 4,5-dihydroisoxazole derivatives 3a,b,c and for the gem-functionalized 4,5-dihydroisoxazoles amino carboxylic ester 5. The β-substituted compounds 1c,d,e, inert to 1,1-dimethylethylnitrile oxide, undergo the reaction to the N,C double bond, thus giving with 2a,b the 4,5-dihydro-1,2,4-oxadiazole derivatives 4. All the reactions occur with high site- and regioselectivity.
  Journal of Heterocyclic Chemistry 03/2009; 29(6):1593 - 1598. · 1.22 Impact Factor
• Article: Short synthesis of tryptophane and β‐carboline derivatives by reaction of indoles with N‐(diphenylmethylene)‐α,β‐didehydroamino acid esters

  Gilberto Spadoni, Cesarino Balsamini, Annalida Bedini, Ermanno Duranti, Andrea Tontini
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  ABSTRACT: The ethylaluminum dichloride catalyzed Michael-type addition of indoles 1a-h to the N-(diphenylmethylene)-α,β-didehydroamino acid esters 2a-c allows a new synthesis of β-methyltryptophanes 41,m and a new route for 1,1-diphenyl-3-carbalkoxy-1,2,3,4-tetrahydro-β-carbolines 5a-m.
  Journal of Heterocyclic Chemistry 03/2009; 29(2):305 - 309. · 1.22 Impact Factor
• Article: Synthesis and characterization of a peripherally restricted CB1 cannabinoid antagonist, URB447, that reduces feeding and body-weight gain in mice.

  Jesse LoVerme, Andrea Duranti, Andrea Tontini, Gilberto Spadoni, Marco Mor, Silvia Rivara, Nephi Stella, Cong Xu, Giorgio Tarzia, Daniele Piomelli
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  ABSTRACT: Cannabinoid CB(1) receptor antagonists reduce body weight in rodents and humans, but their clinical utility as anti-obesity agents is limited by centrally mediated side effects. Here, we describe the first mixed CB(1) antagonist/CB(2) agonist, URB447 ([4-amino-1-(4-chlorobenzyl)-2-methyl-5-phenyl-1H-pyrrol-3-yl](phenyl)methanone), which lowers food intake and body-weight gain in mice without entering the brain or antagonizing central CB(1)-dependent responses. URB447 may provide a useful pharmacological tool for investigating the cannabinoid system, and might serve as a starting point for developing clinically viable CB(1) antagonists devoid of central side effects.
  Bioorganic & medicinal chemistry letters 01/2009; 19(3):639-43. · 2.65 Impact Factor