Diseño y síntesis de nuevos derivados de tiofeno con potencial actividad moduladora alostérica positiva (MAP) del receptor nicotínico de acetilcolina a7 humano.
Loading...
Date
2026
Journal Title
Journal ISSN
Volume Title
Publisher
Universidad de Concepción
Abstract
El receptor nicotínico de acetilcolina subtipo α7 (RnACo α7) representa un blanco terapéutico clave para el abordaje de la enfermedad de Alzheimer por su rol en los procesos de memoria y cognición. En este trabajo se diseñó y sintetizó una serie de 20 compuestos variando la sustitución en el anillo de tiofeno con núcleos de indolina, tetrahidroquinolina y anilina. Las estructuras obtenidas se caracterizaron en su mayoría, mediante espectroscopía de FT-IR y RMN de 1H y 13C. Posteriormente, se evaluó la solubilidad en agua de los compuestos y se determinó su actividad biológica mediante ensayos electrofisiológicos en el receptor, complementando el estudio con análisis bioinformáticos de acoplamiento y dinámica molecular. Como resultados principales, se logró la caracterización de la mayoría de las moléculas y la determinación de la estructura cristalina del compuesto 18 por difracción de rayos X de monocristal. Los ensayos de solubilidad mostraron que solo del 25 al 30 presentó solubilidad parcial. En la evaluación electrofisiológica, únicamente los compuestos 29 y 30 exhibieron un efecto modulador alostérico, aunque de menor magnitud respecto a la respuesta del agonista endógeno. Los estudios de acoplamiento y dinámica molecular, evidenciaron que la afinidad del compuesto por el sitio alostérico está favorecida por interacciones hidrofóbicas, mientras que el control PNU-120596 establece adicionalmente enlaces de hidrógeno. Finalmente, los hallazgos permitieron dar un cumplimiento parcial a la hipótesis planteada. Si bien se logró la ruta sintética, caracterización y evaluación preliminar de los candidatos, las limitaciones de solubilidad encontradas impidieron llevar a cabo la totalidad de los ensayos requeridos para confirmar si estos compuestos actúan de forma definitiva como moduladores alostéricos positivos del humano.
The α7 nicotinic acetylcholine receptor (α7 nAChR) represents a key therapeutic target for Alzheimer’s disease due to its role in memory and cognition. In this study, a series of 20 compounds was designed and synthesized by varying the substitution on the thiophene ring with indoline, tetrahydroquinoline, and aniline cores. The obtained structures were characterized using IR and 1H and 13C NMR spectroscopy. Subsequently, the water solubility of the compounds was evaluated and their biological activity was determined through electrophysiological assays on the human receptor, complemented by molecular docking and molecular dynamics simulations. As for the main results, most of the molecules were successfully characterized, and the crystal structure of compound 18 was determined by single-crystal X-ray diffraction. Solubility assays showed that only compounds 25 to 30 exhibited partial solubility in water. In the electrophysiological evaluation, only compounds 29 and 30 displayed an allosteric modulatory effect, albeit of lower magnitude compared to the response of the endogenous agonist. Molecular docking and dynamics simulations revealed that their interaction within the allosteric site is predominantly mediated by hydrophobic interactions, whereas the reference compound PNU-120596 additionally forms hydrogen bonds. Ultimately, these findings allow for partial fulfillment of the proposed hypothesis. Although the synthetic route, structural characterization, and preliminary evaluation of the candidates were successfully carried out, solubility limitations prevented the completion of the necessary assays to confirm whether these compounds act definitively as positive allosteric modulators of the human α7 nAChR.
The α7 nicotinic acetylcholine receptor (α7 nAChR) represents a key therapeutic target for Alzheimer’s disease due to its role in memory and cognition. In this study, a series of 20 compounds was designed and synthesized by varying the substitution on the thiophene ring with indoline, tetrahydroquinoline, and aniline cores. The obtained structures were characterized using IR and 1H and 13C NMR spectroscopy. Subsequently, the water solubility of the compounds was evaluated and their biological activity was determined through electrophysiological assays on the human receptor, complemented by molecular docking and molecular dynamics simulations. As for the main results, most of the molecules were successfully characterized, and the crystal structure of compound 18 was determined by single-crystal X-ray diffraction. Solubility assays showed that only compounds 25 to 30 exhibited partial solubility in water. In the electrophysiological evaluation, only compounds 29 and 30 displayed an allosteric modulatory effect, albeit of lower magnitude compared to the response of the endogenous agonist. Molecular docking and dynamics simulations revealed that their interaction within the allosteric site is predominantly mediated by hydrophobic interactions, whereas the reference compound PNU-120596 additionally forms hydrogen bonds. Ultimately, these findings allow for partial fulfillment of the proposed hypothesis. Although the synthetic route, structural characterization, and preliminary evaluation of the candidates were successfully carried out, solubility limitations prevented the completion of the necessary assays to confirm whether these compounds act definitively as positive allosteric modulators of the human α7 nAChR.
Description
Tesis presentada para optar al grado de Magíster en Ciencias con mención en Química.
Keywords
Tiofenos, Acetilcolina, Receptores nicotínicos, Enfermedad de Alzheimer