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Facultat de Farmàcia
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Edifici A - Primer pis

Avinguda Joan XXIII s/n
08028 - Barcelona
Telèfon: 93 402 1093
Fax: 93 403 1886

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Alcohol enhances the psychostimulant and conditioning effects of mephedrone in adolescent mice; postulation of unique roles of D3 receptors and BDNF in place preference acquisition

Andrés Ciudad-Roberts, Jorge Camarasa, Carlos J. Ciudad, David Pubill* and Elena Escubedo

* Departament de Farmacologia i Química Terapèutica, Unitat de Farmacologia

Abstract: BACKGROUND AND PURPOSE: The psychostimulant mephedrone is often consumed in combination with alcohol (EtOH). This kind of drug consumption during adolescence is a matter of concern.

EXPERIMENTAL APPROACH: We studied, in adolescent CD-1 mice, whether EtOH could enhance the psychostimulant (locomotor acivity) and rewarding [conditioned place preference (CPP)] effects of mephedrone. We also determined the transcriptional changes associated with aconditioning treatment with these drugs.

KEY RESULTS: Mephedrone (10 mg/kg) increased locomotor activity, which was further enhanced by 40% when combined with EtOH (1 g/kg). This enhancement was blocked by haloperidol. Furthermore, mephedrone (25 mg/kg) induced CPP, which increased by 70% when administered with a dose of EtOH that was not conditioning by itself (0.75 g/kg). There was enhanced expression of the D 3 dopamine receptor mRNA ( Drd3 ) and Arpc5 in all drug-treated groups. The D 3 receptor antagonist SB-277011A and the BDNF receptor antagonist ANA-12 completely prevented CPP as well as the increases in Drd3 in all groups. Accordingly, increased expression of BDNF mRNA in medial prefrontal cortex was detected at 2 and 4 h after mephedrone administration.

CONCLUSIONS AND IMPLICATIONS: If translated to humans, the enhancement of mephedrone effects by ethanol could result in increased abuse liability. D 3 receptors and BDNF play a key role in the establishment of CPP by mephedrone, although an accompanying increase in other synaptic plasticity-related genes may also be necessary.

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Multicomponent reaction-based synthesis and biological evaluation of tricyclic heterofused quinolines with multitrypanosomatid activity

Ornella Di Pietro, Esther Vicente-García, Martin C. Taylor, Diana Berenguer, Elisabet Viayna, Anna Lanzoni, Irene Sola, Helena Sayago, Cristina Riera, Roser Fisa, M. Vicatòria Clos, Belén Pérez, John M. Kelly, Rodolfo Lavilla, and Diego Muñoz-Teorrero*

* Departament de Farmacologia i Química Terapèutica, Unitat de Química Farmacèutica

Abstract: Human African trypanosomiasis (HAT), Chagas disease and leishmaniasis, which are caused by the trypanosomatids Trypanosoma brucei , Trypanosoma cruzi and Leishmania species, are among the most deadly neglected tropical diseases. The development of drugs that are active against several trypanosomatids is appealing from a clinical and economic viewpoint, and seems feasible, as these parasites share metabolic pathways and hence might be treatable by common drugs. From benzonapthyridine 1, an inhibitor of acetylcholinesterase (AChE) for which we have found a remarkable trypanocidal activity, we have designed and synthesized novel benzo[ h ][1,6]naphthyridines, pyrrolo[3,2- c ]quinolines, azepino [3,2- c ]quinolines, and pyrano[3,2- c ]quinolines through 2-4-step sequences featuring an initial multicomponent Povarov reaction as the key step. To assess the therapeutic potential of the novel compounds, we have evaluated their in vitro activity against T. brucei , T. cruzi , and Leishmania infantum , as well as their brain permeability, which is of specific interest for the treatment of late-stage HAT. To assess their potential toxicity, we have determined their cytotoxicity against rat myoblast L6 cells and their AChE inhibitory activity. Several tricyclic heterofused quinoline derivatives were found to display an interesting multi-trypanosomatid profile, with one-digit micromolar potencies against two of these parasites and two-digit micromolar potency against the other. Pyranoquinoline 39, which displays IC 50 values of 1.5 uM, 6.1 uM and 29.2 uM against T. brucei , L. infantum and T. cruzi , respectively, brain permeability, better drug-like properties (lower lipophilicity and molecular weight and higher CNS MPO desirability score) than hit 1, and the lowest AChE inhibitory activity of the series (IC 50 > 30 uM), emerges as an interesting multi-trypanosomatid lead, amenable to further optimization particularly in terms of its selectivity index over mammalian cells.

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Effect of polypurine reverse Hoogsteen hairpins on relevant cancer target genes in different human cell lines

Xenia Villalobos, Laura Rodríguez, Anna Solé, Carolina Lliberós Núria Mencia, Carlos J. Ciudad*, Véronique Noé

* Departament de Bioquímica i Biologia Molecular

Abstract: We studied the ability of polypurine reverse Hoogsteen hairpins (PPRHs) to silence a variety of relevant cancerrelated genes in several human cell lines. PPRHs are hairpins formed by two antiparallel polypurine strands bound by intramolecular Hoogsteen bonds linked by a pentathymidine loop. These hairpins are able to bind to their target DNA sequence through Watson–Crick bonds producing specific silencing of gene expression. We designed PPRHs against the following genes: BCL2 , TOP1 , mTOR , MDM2 , and MYC and tested them for mRNA levels, cytotoxicity, and apoptosis in prostate, pancreas, colon, and breast cancer cell lines. Even though all PPRHs were effective, the most remarkable results were obtained with those against BCL2 and mammalian target of rapamycin (mTOR) in decreasing cell survival and mRNA levels and increasing apoptosis in prostate, colon, and pancreatic cancer cells. In the case of TOP1, MDM2, and MYC, their corresponding PPRHs produced a strong effect in decreasing cell viability and mRNA levels and increasing apoptosis in breast cancer cells. Thus, we confirm that the PPRH technology is broadly useful to silence the expression of cancer-related genes as demonstrated using target genes involved in metabolism ( DHFR ), proliferation ( mTOR ), DNA topology ( TOP1 ), lifespan and senescence ( telomerase ), apoptosis ( survivin , BCL2 ), transcription factors (MYC), and proto-oncogenes ( MDM2 ).

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Environmental enrichment improves behavior, cognition and brain functional markers in young senescence-accelerated prone mice (SAMP8)

Christina Griñan-Ferré, David Pérez-Cáceres, Sofía Martínez Guitérrez-Zetina, Antoni Camins, Verónica Palomera-Avalos, Daniel Ortuño-Sahagún, M. Teresa Rodrigo and M. Pallàs*

* Departament de Farmacologia i Química Terapèutica, Unitat de Farmacologia

Abstract: The environment in which organisms live can greatly influence their development. Consequently, environmental enrichment (EE) is progressively recognized as an important component in the improvement of brain function and development. It has been demonstrated that rodents raised under EE conditions exhibit favorable neuroanatomical effects that improve their learning, spatial memory, and behavioral performance. Here, by using senescence-accelerated prone mice (SAMP8) and these as a model of adverse genetic conditions for brain development, we determined the effect of EE by raising these mice during early life under favorable conditions. We found a better generalized performance of SAMP8 under EE in the results of four behavioral and learning tests. In addition, we demonstrated broad molecular correlation in the hippocampus by an increase in NeuN and Ki67 expression, as well as an increase in the expression of neurotrophic factors, such as pleiotrophin (PTN) and brain-derived neurotrophic factor (BDNF), with a parallel decrease in neurodegenerative markers such as GSK3, amyloid-beta precursor protein, and phosphorylated beta-catenin, and a reduction of SBDP120, Bax, GFAP, and interleukin-6 (IL-6), resulting in a neuroprotective panorama. Globally, it can be concluded that EE applied to SAMP8 at young ages resulted in epigenetic regulatory mechanisms that give rise to significant beneficial effects at the molecular, cellular, and behavioral levels during brain development, particularly in the hippocampus.

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Novel levetiracetam derivatives that are effective against the Alzheimer-like phenotype in mice: Synthesis, in vitro, ex vivo, and in vivo efficacy studies

Irene Sola, Ester Aso, Daniela Frattini, Irene López-González, Alba Espargaró, Raimon Sabaté, Ornella Di Pietro, F. Javier Luque, M. Victòria Clos, Isidro Ferrer, Diego Muñoz-Torrero*

* Departament de Farmacologia i Química Terapèutica, Unitat de Química Farmacèutica

Abstract: We have synthesized a series of heptamethylene-linked levetiracetam - huprine and levetiracetam - (6-chloro)tacrine hybrids to hit amyloid, tau, and cholinergic pathologies as well as ß-amyloid (Aß)-induced epileptiform activity, some of the mechanisms that eventually lead to cognitive deficits in Alzheimer's disease patients. These hybrids are potent inhibitors of human acetylcholinesterase and butyrylcholinesterase in vitro and moderately potent Aß42 and tau antiaggregating agents in a simple E. coli model of amyloid aggregation. Ex vivo determination of the brain acetylcholinesterase inhibitory activity of these compounds after intraperitoneal injection to C57BL6J mice has demonstrated their ability to enter the brain. The levetiracetam - huprine hybrid 10 significantly reduced the incidence of epileptic seizures, cortical amyloid burden, and neuroinflammation in APP/PS1 mice after a 4-week treatment with a 5 mg/kg dose. Moreover, the hybrid 10 rescued transgenic mice from cognitive deficits, thereby emerging as an interesting disease-modifying anti-Alzheimer drug candidate.

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Synthesis, biological profiling and mechanistic studies of 4-aminoquinoline-based heterodimeric compounds with dual trypanocidal-antiplasmodial activity

Irene Sola, Sílvia Castellà, Elisabet Viayna, Carles Galdeano, Martin C. Taylor, Stephen Y. Gbedema, Belén Pérez, M. Victòria Clos, Deuan C. Jones, Alan H. Fairlamb, Colin W. Wright, John M. Kelly, Diego Muñoz-Torrero*

* Departament de Farmacologia i Química Terapèutica, Unitat de Química Farmacèutica

Abstract: Dual submicromolar trypanocidal-antiplasmodial compounds have been identified by screening and chemical synthesis of 4-aminoquinoline-based heterodimeric compounds of three different estructural classes. In Trypanosoma brucei , inhibition of the enzyme trypanothione reductase seems to be involved in the potent trypanocidal activity of these heterodimers, although it is probably not the main biological target. Regarding antiplasmodial activity, the heterodimers seem to share the mode of action of the antimalarial drug chloroquine, which involves inhibition of the haem detoxification process. Interestingly, all of these heterodimers display good brain permeabilities, thereby being potentially useful for late stage human African trypanosomiasis. Future optimization of these compounds should focus mainly on decreasing cytotoxicity and acetylcholinesterase inhibitory activity.

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A bioinspired peptide scaffold with high antibiotic activity and low in vivo toxicity

Francesc Rabanal, Ariadna Grau-Campistany, Xavier Vila-Farrés, Javier González-Linares, Miquel Borràs, Jordi Vila, Ángeles Manresa, Yolanda Cajal*

* Departament de Fisicoquímica

Abstract: Bacterial resistance to almost all available antibiotics is an important public health issue. A major goal in antimicrobial drug discovery is the generation of new chemicals capable of killing pathogens with high selectivity, particularly multi-drug-resistant ones. Here we report the design, preparation and activity of new compounds based on a tunable, chemically accessible and upscalable lipopeptide scaffold amenable to suitable hit-to-lead development. Such compounds could become therapeutic candidates and future antibiotics available on the market. The compounds are cyclic, contain two D-amino acids for in vivo stability and their structures are reminiscent of other cyclic disulfide-containing peptides available on the market. The optimized compounds prove to be highly active against clinically relevant Gram-negative and Gram-positive bacteria. In vitro and in vivo tests show the low toxicity of the compounds. Their antimicrobial activity against resistant and multidrugresistant bacteria is at the membrane level, although other targets may also be involved depending on the bacterial strain.

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Easy access to (2-imidazolin-4-yl)phosphonates by a microwave assisted multicomponent reaction

Sonia Abàs, Carolina Estarellas, F.Javier Luque, Carmen Escolano*

* Departament de Farmacologia i Química Terapèutica, Unitat de Química Orgànica

Abstract: An efficient and user-friendly synthetic process involving the combination of multicomponent reaction methodology and microwave heating generates unprecedented (2-imidazolin-4-yl)phosphonates 1-18. This strategy presents a silver-catalysed, operationally simple and environmentally friendly transformation without the need of anhydrous atmosphere or additional solvents.

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Outer-inner membrane vesicles naturally secreted by Gram-negative pathogenic bacteria

Carla Pérez-Cruz, Lidia Delgado, Carmen López-Iglesias, E. Mercadé*

* Departament de Microbiologia i Parasitologia Sanitàries, Unitat de Microbiologia

Abstract: Outer-inner membrane vesicles (O-IMVs) were recently described as a new type of membrane vesicle secreted by the Antarctic bacterium Shewanella vesiculosa M7T. Their formation is characterized by the protrusion of both outer and plasma membranes, which pulls cytoplasmic components into the vesicles. To demonstrate that this is not a singular phenomenon in a bacterium occurring in an extreme environment, the identification of O-IMVs in pathogenic bacteria was undertaken. With this aim, a structural study by Transmission Electron Microscopy (TEM) and Cryo-transmission electron microscopy (Cryo-TEM) was carried out, confirming that O-IMVs are also secreted by Gram-negative pathogenic bacteria such as Neisseria gonorrhoeae , Pseudomonas aeruginosa PAO1 and Acinetobacter baumannii AB41, in which they represent between 0.23% and 1.2% of total vesicles produced. DNA and ATP, which are components solely found in the cell cytoplasm, were identified within membrane vesicles of these strains. The presence of DNA inside the O-IMVs produced by N. gonorrhoeae was confirmed by gold DNA immunolabeling with a specific monoclonal IgM against double-stranded DNA. A proteomic analysis of N. gonorrhoeae -derived membrane vesicles identified proteins from the cytoplasm and plasma membrane. This confirmation of O-IMV extends the hitherto uniform definition of membrane vesicles in Gram-negative bacteria and explains the presence of components in membrane vesicles such as DNA, cytoplasmic and inner membrane proteins, as well as ATP, detected for the first time. The production of these O-IMVs by pathogenic Gram-negative bacteria opens up new areas of study related to their involvement in lateral gene transfer, the transfer of cytoplasmic proteins, as well as the functionality and role of ATP detected in these new vesicles .

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A novel pathway producing dimethylsulphide in bacteria is widespread in soil environments

O. Carrión, A.R.J. Curson, D. Kumaresan, Y. Fu, A.S. Lang, E. Mercadé*, J.D. Tood

* Departament de Microbiologia i Parasitologia Sanitàries, Unitat de Microbiologia

Abstract: The volatile compound dimethylsulphide (DMS) is important in climate regulation, the sulphur cycle and signalling to higher organisms. Microbial catabolism of the marine osmolyte dimethylsulphoniopropionate (DMSP) is thought to be the major biological process generating DMS. Here we report the discovery and characterization of the first gene for DMSP-independent DMS production in any bacterium. This gene, mddA , encodes a methyltransferase that methylates methanethiol and generates DMS. MddA functions in many taxonomically diverse bacteria including sediment-dwelling pseudomonads, nitrogen-fixing bradyrhizobia and cyanobacteria, and mycobacteria including the pathogen Mycobacterium tuberculosis . The mddA gene is present in metagenomes from varied environments, being particularly abundant in soil environments, where it is predicted to occur in up to 76% of bacteria. This novel pathway may significantly contribute to global DMS emissions, especially in terrestrial environments and could represent a shift from the notion that DMSP is the only significant precursor of DMS.

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  © Universitat de Barcelona Edició: Secretaria d'Estudiants i Docència Facultat de Farmàcia
Última actualització o validació:06.11.2015