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Characterization of the 5-HT7 receptor as a new therapeutic target for the treatment of pain Àlex Brenchat Barberà ADVERTIMENT. La consulta d’aquesta tesi queda condicionada a l’acceptació de les següents condicions d'ús: La difusió d’aquesta tesi per mitjà del servei TDX (www.tdx.cat) ha estat autoritzada pels titulars dels drets de propietat intel·lectual únicament per a usos privats emmarcats en activitats d’investigació i docència. No s’autoritza la seva reproducció amb finalitats de lucre ni la seva difusió i posada a disposició des d’un lloc aliè al servei TDX. No s’autoritza la presentació del seu contingut en una finestra o marc aliè a TDX (framing). Aquesta reserva de drets afecta tant al resum de presentació de la tesi com als seus continguts. En la utilització o cita de parts de la tesi és obligat indicar el nom de la persona autora. ADVERTENCIA. La consulta de esta tesis queda condicionada a la aceptación de las siguientes condiciones de uso: La difusión de esta tesis por medio del servicio TDR (www.tdx.cat) ha sido autorizada por los titulares de los derechos de propiedad intelectual únicamente para usos privados enmarcados en actividades de investigación y docencia. No se autoriza su reproducción con finalidades de lucro ni su difusión y puesta a disposición desde un sitio ajeno al servicio TDR. No se autoriza la presentación de su contenido en una ventana o marco ajeno a TDR (framing). Esta reserva de derechos afecta tanto al resumen de presentación de la tesis como a sus contenidos. En la utilización o cita de partes de la tesis es obligado indicar el nombre de la persona autora. WARNING. On having consulted this thesis you’re accepting the following use conditions: Spreading this thesis by the TDX (www.tdx.cat) service has been authorized by the titular of the intellectual property rights only for private uses placed in investigation and teaching activities. Reproduction with lucrative aims is not authorized neither its spreading and availability from a site foreign to the TDX service. Introducing its content in a window or frame foreign to the TDX service is not authorized (framing). This rights affect to the presentation summary of the thesis as well as to its contents. In the using or citation of parts of the thesis it’s obliged to indicate the name of the author. Characterization of the 5-HT7 receptor as a new therapeutic target for the treatment of pain Doctoral Thesis 2012 The work showed in this Thesis has been part of the “5-HT7 and neuropathic pain” project in the pharmaceutical company Esteve. Thus, the aim of this thesis was in line with the goal of the 5-HT7 project at Esteve focused on drug discovery of 5-HT7 ligands for the treatment of neuropathic pain. Taking the advantage of a genetic approach (5-HT7 receptor knockout mice) and pharmacological tools (5-HT7 receptor ligands) we investigated at the preclinical level the role of 5-HT7 receptors in nociception and the therapeutic interest of 5-HT7 ligands on pain treatment. This Thesis adds better knowledge to the role of 5-HT7 receptors in the control of pain and point to a new potential use of 5-HT7 receptor agonists as promising drugs for the treatment of neuropathic pain. receptor as a new therapeutic target for the treatment of pain 7 Characterization of the 5-HT Àlex Brenchat Barberà Doctoral Thesis 2012 Àlex Barberà Brenchat Characterization of the 5-HT7 receptor as a new therapeutic target for the treatment of pain Àlex Brenchat Barberà Departament de Bioquímica i Biologia Molecular Facultat de Biologia Universitat de Barcelona 2012 Programa de Doctorat de Biomedicina. Bienni 2005-2007 Departament de Bioquímica i Biologia Molecular Facultat de Biologia, Universitat de Barcelona Characterization of the 5-HT7 receptor as a new therapeutic target for the treatment of pain Caracterització del receptor 5-HT7 com a diana terapèutica pel tractament del dolor Memòria per optar al grau de Doctor per la Universitat de Barcelona Els resultats experimentals d’aquesta Tesi han estat obtinguts a Laboratorios Dr. Esteve Àlex Brenchat Barberà Autor Dr. José Miguel Vela Dra. Luz Romero Dr. Antonio Zorzano Hernández Alonso Olarte Director Codirectora Tutor Dedicat a la meva família i amics Agraïments: Primer de tot voldria agrair als Laboratoris Dr. Esteve per la possibilitat de treballar en una empresa farmacèutica tant prestigiosa i familiar al mateix temps. Començar la meva vida laboral recent llicenciat en una empresa com Esteve va ser per mi un repte molt important que vaig prendre amb molta il·lusió i responsabilitat. Concretament la possibilitat de treballar en la validació de dianes terapèutiques amb la finalitat de desenvolupar futurs i innovadors fàrmacs pel tractament del dolor segueix sent per mi una gran oportunitat. Per posar en antecedents, vaig estudiar Biologia Humana a la Universitat Pompeu Fabra (UPF). La llicenciatura de Biologia que tot just havia començat aquell any a la UPF estava especialment enfocada a la investigació Biomèdica. Sempre he tingut molt despert l’interès per conèixer i investigar l’ésser humà i la consistència de la vida. La meva curiositat innata per explorar el món, juntament amb la mort del meu avi Ramon de càncer als 50 anys quan jo era molt petit, crec que són els dos principals factors que expliquen la meva clara vocació d’investigador científic. Durant els 7 anys treballant a Esteve he conegut moltes persones que m’han ajudat a créixer tant a nivell personal com professional. Voldria agrair a totes les persones d’Esteve i concretament del departament de Farmacologia per tots els moments sobretot bons que he compartit amb tots ells. També voldria donar les gràcies, especialment, a cadascuna de les persones que varen formar part del departament de Target Validation, on vaig realitzar la major part d’aquesta Tesi doctoral: Georgia Gris, Beatriz de la Puente, Enrique Portillo, Ricard Sánchez, Luz Romero, Javier Burgueño, Sergio Ovalle, Daniel Zamanillo i José Miguel Vela. És d’agrair la relació amb tots ells pel treball en equip, per l’elevat nivell i rigor científic i sobretot per compartir tants moments extraordinaris. Voldria agrair al meu director de Tesi, el José Miguel Vela per la confiança dipositada en mi des de que vaig entrar a treballar a Esteve. Del José Miguel he après la metodologia de treballar per objectius. L’entusiasme i passió per la investigació que caracteritzen al José Miguel m’ha donat la força necessària per seguir endavant en moments de dificultats. També ha estat molt important el treball en equip amb la meva codirectora de Tesi, la Luz Romero, qui com a líder del projecte 5-HT7 juntament amb la seva professionalitat i rigor científic m’ha guiat en el disseny i realització dels experiments d’aquesta Tesi. A més, voldria agrair a l’Antonio Zorzano, investigador de la Universitat de Barcelona, per brindar-se a ser el tutor de la meva Tesi. Durant aquests anys de formació a nivell professional voldria agrair també a aquelles persones que hi han contribuït significativament: Jordi Quintana, Rafael Maldonado, Joaquim Gea, Fèlix Bosch, Josep-Eladi Baños i Joan Bigorra. Moltes gràcies també a tots els amics que han estat involucrats en un projecte de Tesi doctoral: Anna Garriga, Clara Valls, Juan Rojo, Francesc Vives, Sonia Conesa, Jorge Martínez, Oriol Nicolás, Daniel del Toro, Joan Aicart i Maria Chiara Conidi. I a tants altres amics que m’han acompanyat durant tot aquest temps: Josep Coves, Josep Maria Mazarico, Joan Alsina, Anna Aliaga, Enric Seda, Marta Sánchez, Alba Subirana, Fabio Amanqui, Joel Cervera, Lluís Seguí, Pedro Pablo, Imma Navas, Albert Seda, Néstor García, Mar Lopategui, Ignasi Lisicic; als amics de la música: Jordi Benedico, David Folch, Sonia Barea, David Vallès, Manel Barea, Alfons Reverté; i als amics de l’ONG Banc Farmacèutic: Eleonora Lasagna, Marcello Perego, Josep Maria Puigjaner, Carlos Guerrero, Valentín de Grado, María García, Carlota Soler, Màbel Torroja, Mercè Garrigosa… Voldria també fer especial menció als meus pares José Tomás i Maria José per haver-me donat la vida i així poder viure experiències tant inoblidables com la realització d’una Tesi doctoral. La seva confiança dipositada en el meu desig ha fet realitat el somni d’arribar a ser un investigador científic. L’afecte i educació que he rebut de tota la meva família ha estat el pilar per al meu desenvolupament personal i professional, en aquest sentit voldria agrair especialment: al meu germà Raül i a la Vanessa a qui els hi desitjo el millor en la seva vida personal i professional; als meus avis Elena, Ramón, Blas i Antonia; als meus tiets Carme, Josep Àngel, Laura, Dani, Tere, Francesc, la meva padrina Mercè; als meus cosins Anna, Sara, Marc, Laia i Estela; i a la meva familia política, la iaia Maria, els meus sogres Toni i Juani i els meus cunyats. Especialment voldria acabar aquests agraïments manifestant la importància que ha tingut la meva dona en la realització d’aquesta Tesi. De la Marta he rebut el seu suport en tot moment, i el que és més important un amor incondicional que m’ha donat la força per arriscar i seguir apostant per aquells reptes que la vida m’ha anat posant davant. A casa ja som quatre amb els nostres fills, el Pau de 3 anys i el Jordi d’1 any. A tots el qui ja formeu part de la meva història no us puc més que agrair i respondre amb el mateix afecte que jo he rebut. Gràcies! “The most beautiful thing we can experience is the mysterious. It is the source of all true art and all science.
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  • Screening of Clinically Approved and Investigation Drugs As Potential

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    Screening of Clinically Approved and Investigation Drugs as Potential Inhibitors of COVID-19 Main Protease: A Virtual Drug Repurposing Study Serdar Durdagi1,*, Busecan Aksoydan1,2, Berna Dogan1, Kader Sahin1, Aida Shahraki1,3 1Computational Biology and Molecular Simulations Laboratory, Department of Biophysics, School of Medicine, Bahcesehir University, Istanbul, Turkey 2Neuroscience Program, Graduate School of Health Sciences, Bahçeşehir University, Istanbul, Turkey 3Department of Molecular Biology and Genetics, Bogazici University, Istanbul, Turkey Abstract There is an urgent need for a new drug against COVID-19. Since designing a new drug and testing its pharmacokinetics and pharmacodynamics properties may take years, here we used a physics-driven high throughput virtual screening drug re-purposing approach to identify new compounds against COVID-19. As the molecules considered in repurposing studies passed through several stages and have well-defined profiles, they would not require prolonged pre- clinical studies and hence, they would be excellent candidates in the cases of disease emergencies or outbreaks. While the spike protein is the key for the virus to enter the cell though the interaction with ACE2, enzymes such as main protease are crucial for the life cycle of the virus. This protein is one of the most attractive targets for the development of new drugs against COVID-19 due to its pivotal role in the replication and transcription of the virus. We used 7922 FDA approved small molecule drugs as well as compounds in clinical investigation from NIH Chemical Genomics Center (NCGC) Pharmaceutical Collection (NPC) database in our drug repurposing study. Both apo and holo forms of target protein COVID-19 main proteases were used in virtual screening.
  • Customs Tariff - Schedule

    Customs Tariff - Schedule

    CUSTOMS TARIFF - SCHEDULE 99 - i Chapter 99 SPECIAL CLASSIFICATION PROVISIONS - COMMERCIAL Notes. 1. The provisions of this Chapter are not subject to the rule of specificity in General Interpretative Rule 3 (a). 2. Goods which may be classified under the provisions of Chapter 99, if also eligible for classification under the provisions of Chapter 98, shall be classified in Chapter 98. 3. Goods may be classified under a tariff item in this Chapter and be entitled to the Most-Favoured-Nation Tariff or a preferential tariff rate of customs duty under this Chapter that applies to those goods according to the tariff treatment applicable to their country of origin only after classification under a tariff item in Chapters 1 to 97 has been determined and the conditions of any Chapter 99 provision and any applicable regulations or orders in relation thereto have been met. 4. The words and expressions used in this Chapter have the same meaning as in Chapters 1 to 97. Issued January 1, 2019 99 - 1 CUSTOMS TARIFF - SCHEDULE Tariff Unit of MFN Applicable SS Description of Goods Item Meas. Tariff Preferential Tariffs 9901.00.00 Articles and materials for use in the manufacture or repair of the Free CCCT, LDCT, GPT, UST, following to be employed in commercial fishing or the commercial MT, MUST, CIAT, CT, harvesting of marine plants: CRT, IT, NT, SLT, PT, COLT, JT, PAT, HNT, Artificial bait; KRT, CEUT, UAT, CPTPT: Free Carapace measures; Cordage, fishing lines (including marlines), rope and twine, of a circumference not exceeding 38 mm; Devices for keeping nets open; Fish hooks; Fishing nets and netting; Jiggers; Line floats; Lobster traps; Lures; Marker buoys of any material excluding wood; Net floats; Scallop drag nets; Spat collectors and collector holders; Swivels.