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Trabajo De Diploma Facultad de Química-Farmacia Departamento de Farmacia Trabajo de diploma Título: Evaluación experimental “in vivo” de nuevos compuestos con actividad analgésica seleccionados a través del tamizaje virtual. Autor: Yulier León Mederos Tutores: Dr. Yovani Marrero Ponce MSc. Arelis López Sacerio 2009-2010 Exergo Todos y cada uno de nosotros paga puntualmente su cuota de sacrificio consciente de recibir el premio en la satisfacción del deber cumplido, conscientes de avanzar con todos hacia el Hombre Nuevo que se vislumbra en el horizonte... Che Yulier León Mederos Evaluación experimental “in vivo” de nuevos compuestos con actividad analgésica seleccionados a través del tamizaje virtual Dedicatoria A alguien que se lo merece, por su ayuda y su apoyo durante esta larga carrera como estudiante universitario, mi madre la cual confió siempre en mí y por ver esperado con paciencia esta gran hazaña. Elisa Jorge por verse convertido en mi madre y por su apoyo incondicional cada día que transcurrió en esta escuela. A mis hermanos por estar siempre a mí lado cuando más yo los necesitaba, a mi abuela que no pudo disfrutar esta gran victoria junto a mí, pero allá donde ella está le llegará este lindo regalo. Yulier León Mederos Evaluación experimental “in vivo” de nuevos compuestos con actividad analgésica seleccionados a través del tamizaje virtual Agradecimientos Esta página está dedicada a todas aquellas personas que de un modo u otro hicieron posible la realización de esta tesis. Quisiera agradecer en primer lugar a mi madre que siempre depositó todo su amor y confianza en mí, sobre todo en los momentos difíciles a lo largo de mi carrera A mis hermanos ya que sus consejos siempre fueron buenos y por el aprecio que siento hacia ellos. De forma muy especial a mi tutora por su ayuda, a Elisa por verme guiado por el camino de la verdad y al profesor Mario por su ayuda y entrega durante la realización de la parte experimental. A mi novia la cual quiero mucho ya que siempre ha estado en los momentos buenos y malos a mi lado, a su mamá por su ayuda incondicional en tan poco tiempo, su hermano y su cuñada por toda la ayuda que me dieron. A todos mis compañeros de aula por los momentos buenos que pasé junto a ellos, en especial a Sayli, Yanniel, Yunieski, Junier y Yankiel que fueron mis amigos inseparables. De igual manera a Lili una amiga la cual aprecio mucho por su voluntad, y a todas sus compañeras de cuarto. A Jorge y su abuela Ana por verme ayudado en gran parte de la vida como estudiante universitario. A toda mi familia y en especial a mi abuelita que siempre confió en mí y sabía que yo podía cumplir la meta. A todos muchas gracias Yulier León Mederos Evaluación experimental “in vivo” de nuevos compuestos con actividad analgésica seleccionados a través del tamizaje virtual Glosario λ Lambda de Wilks ΔP% Porcentaje de Clasificación 5-HT Serotonina AINEs Antiinflamatorios no esteroideos ADL Análisis Discrimintante Lineal ADME Absorción, Distribución, Metabolismo y Excreción ADT Antidepresivos Tricíclicos ARN Acido Ribonucleico AC Análisis de Cluster COX Ciclooxigenasa HETE Heterogéneo CARDD Computed-Aided ‘Rational’ Drug Design D2 Distancia de Mahalanobis DMs Descriptores Moleculares Ec. Ecuación F Fisher FC Función de Clasificación FD Función Discriminante IL-6 Interleuquina 6 k-MCA Análisis de cluster de k-medias Glosario NA Noradrenalina OFQ Orfalina FQ PGs Prostaglandinas PAG Periacueducto gris QSAR Quantitative Structure Activity Relationship SE Serie de Entrenamiento SP Serie de Predicción SNC Sistema Nerviosa Central SG Sustancia gris TOMOCOMD TOpological MOlecular COMputer Design ADNc Acido desoxirribonucleico complementario GRD Ganglio de la raíz dorsal TTX Tetrodotoxina TTX-s Tetrodotoxina sensible TTX-r Tetrodotoxina resistente PGH2 Endoperóxidos Pág. RESUMEN GLOSARIO INTRODUCCIÓN.-------- ----------------------------------------------------------------------------------------- 1 REVISIÓN BIBLIOGRÁFICA.------------------------------------------------------------------------------- 4 1.1 Dolor.----------------------------------------------------------------------------------------------------- 4 1.1.2 Fisiología del Dolor.-------------------------------------------------------------------------------- 5 1.3 Mediadores químicos.------------------------------------------------------------------------------- 10 1.4 Sistema opiode.---------------------------------------------------------------------------------------- 12 1.4.1 Receptrores opiodes.------------------------------------------------------------------------------- 13 1.4.2 Péptidos Endógenos.------------------------------------------------------------------------------ 16 1.5 Dianas involucradas en el dolor.------------------------------------------------------------------ 18 1.6 Fármacos Analgésicos.------------------------------------------------------------------------------- 31 1.6.1 Analgésicos opiáceos.----------------------------------------------------------------------------- 31 1.6.2 Mecanismo de acción.----------------------------------------------------------------------------- 33 1.6.2.1 Propiedades Farmacológicas.----------------------------------------------------------------- 34 1.6.3 Reacciones Adversas.----------------------------------------------------------------------------- 35 1.6.4 Relación Estructura Actividad.------------------------------------------------------------------- 35 1.6.5 Otros fármacos analgésicos.--------------------------------------------------------------------- 41 1.7 Evaluación “in vivo “de la actividad analgésica.----------------------------------------------- 43 1.7.1 Métodos “in vivo” para la determinación de la actividad analgésica. 43 MATERIALES Y METODOS.---------------------------------------------------------------------------------- 50 2.1. Ensayos in silico.--------------------------------------------------------------------------------------- 50 2.1.1 Generalidades.---------------------------------------------------------------------------------------- 50 2.1.2 Base de datos de los compuestos usados en la obtención de los modelos ADL- 50 QSAR (Análisis Discriminante Lineal -Quantitative Structure Activity Relationship). 2.2 Cálculo de los nuevos descriptores moleculares. TOMOCOMD-CARDD Software. 53 2.3. Análisis Estadístico de los Datos: Desarrollo de las Funciones Discriminantes 56 (FDs) usando ADL. 2.4 Identificación/Selección “in silico” de compuestos con actividad analgésica.----------- 57 2.5 Ensayos in vivo.----------------------------------------------------------------------------------------- 58 2.5.1 Test de placa caliente.------------------------------------------------------------------------------- 58 2.5.2 Test de contorsiones.-------------------------------------------------------------------------------- 59 Resultados y Discusión. -------------------------------------------------------------------------------------- 61 3.1 Desarrollo de Modelos QSAR-ADL.---------------------------------------------------------------- 61 3.2 Identificación de Nuevas Entidades Moleculares como Analgésicos utilizando los 80 ________________________________________________________________________ Modelos in silico: El tamizaje Virtual como una Promisoria Alternativa para la Selección y el Diseño Racional de Fármacos Analgésicos. 3.3 Evaluación “in vivo” de la actividad analgésica.------------------------------------------------- 82 CONCLUSIONES.------------------------------------------------------------------------------------------------- 88 RECOMENDACIONES.------------------------------------------------------------------------------------------ 89 REFERENCIAS BIBLIOGRAFICAS.------------------------------------------------------------------------- 90 ________________________________________________________________________ Resumen El tratamiento del dolor asociado a patologías como el cáncer, infarto agudo del miocardio y enfermedades músculo-esqueléticas continúa siendo uno de los más importantes problemas de salud. En este trabajo el objetivo fundamental es identificar computacionalmente mediante el programa TOMOCOMD-CARDD y luego corroborar experimentalmente a través de test “in vivo” nuevos candidatos analgésicos. En este sentido, se emplea una amplia base de datos para la obtención de los índices lineales, bilineales y cuadráticos estocásticos y no estocásticos basados en relaciones de átomo y enlace desarrollándose 72 modelos QSAR-ADL. Los modelos obtenidos fueron utilizados en el cribado virtual de compuestos mediante el cual se identificaron varios fármacos utilizados en la terapéutica actual con otros usos farmacológicos y compuestos sintetizados por diferentes laboratorios como posibles analgésicos. Finalmente se evaluaron 4 compuestos de síntesis (VAM 10,11, 12 y 2-4) a dosis de 100, 150 y 200 mg/Kg mediante el test de Plato caliente y Contorsiones inducidas por ácido acético. Todos ellos mostraron actividad analgésica comparable al control en el test de plato caliente y contorsiones inducidas por ácido acético. Por lo tanto podemos concluir que el método TOMOCOMD-CARDD y el desarrollo de los modelos QSAR-ADL propuestos en este trabajo permiten la identificación/selección de nuevos compuestos con actividad analgésica, corroborada experimentalmente por modelos “in vivo” Yulier León Mederos Evaluación experimental “in vivo” de nuevos compuestos con actividad analgésica seleccionados a través del tamizaje virtual Introducción 1 El dolor, su estudio y su alivio es uno de los temas fundamentales en el ámbito
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