RESUMEN
'A peculiar severe disease process of the cerebral cortex' are the exact words used by A. Alzheimer in 1906 to describe a patient's increasingly severe condition of memory loss, changes in personality, and sleep disturbance. A century later, this 'peculiar' disease has become widely known as Alzheimer's disease (AD), the world's most common neurodegenerative disease, affecting more than 35 million people globally. At the same time, its pathology remains unclear and no successful treatment exists. Several theories for AD etiology have emerged throughout the past century. In this review, we focus on the metabolic mechanisms that are similar between AD and metabolic diseases, based on the results from genome-wide association studies. We discuss signaling pathways involved in both types of disease and look into new optogenetic methods to study the in vivo mechanisms of AD.
Asunto(s)
Enfermedad de Alzheimer/metabolismo , Corteza Cerebral/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Glucosa/metabolismo , Fármacos Neuroprotectores/uso terapéutico , Transducción de Señal/genética , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/genética , Péptidos beta-Amiloides/metabolismo , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/patología , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/patología , Inhibidores de la Dipeptidil-Peptidasa IV/uso terapéutico , Regulación de la Expresión Génica , Glucógeno Sintasa Quinasa 3 beta/genética , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Humanos , Insulina/metabolismo , Resistencia a la Insulina , Metformina/uso terapéutico , Optogenética/métodos , Estrés Oxidativo/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Compuestos de Sulfonilurea/uso terapéutico , Proteínas tau/genética , Proteínas tau/metabolismoRESUMEN
Compounds with activity at serotonin (5-hydroxytryptamine) 5-HT2 and α1 adrenergic receptors have potential for the treatment of central nervous system disorders, drug addiction or overdose. Isolaureline, dicentrine and glaucine enantiomers were synthesized, and their in vitro functional activities at human 5-HT2 and adrenergic α1 receptor subtypes were evaluated. The enantiomers of isolaureline and dicentrine acted as antagonists at 5-HT2 and α1 receptors with (R)-isolaureline showing the greatest potency (pKb = 8.14 at the 5-HT2C receptor). Both (R)- and (S)-glaucine also antagonized α1 receptors, but they behaved very differently to the other compounds at 5-HT2 receptors: (S)-glaucine acted as a partial agonist at all three 5-HT2 receptor subtypes, whereas (R)-glaucine appeared to act as a positive allosteric modulator at the 5-HT2A receptor.
Asunto(s)
Aporfinas/química , Receptor de Serotonina 5-HT2A/metabolismo , Receptores Adrenérgicos alfa 1/metabolismo , Serotonina/química , Agonistas de Receptores Adrenérgicos alfa 1/química , Agonistas de Receptores Adrenérgicos alfa 1/metabolismo , Aporfinas/metabolismo , Sitios de Unión , Células HEK293 , Humanos , Cinética , Simulación del Acoplamiento Molecular , Estructura Terciaria de Proteína , Receptor de Serotonina 5-HT2A/química , Receptor de Serotonina 5-HT2A/genética , Receptores Adrenérgicos alfa 1/química , Receptores Adrenérgicos alfa 1/genética , Serotonina/metabolismo , Agonistas del Receptor de Serotonina 5-HT2/química , Agonistas del Receptor de Serotonina 5-HT2/metabolismo , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
[This corrects the article DOI: 10.1039/C7MD00629B.].
RESUMEN
In this study, the (S)-enantiomers of the aporphine alkaloids, nuciferine and roemerine, were prepared via a synthetic route involving catalytic asymmetric hydrogenation and both stereoisomers were evaluated in vitro for functional activity at human 5-HT2 and adrenergic α1 receptor subtypes using a transforming growth factor-α shedding assay. Both enantiomers of each of the compounds were found to act as antagonists at 5-HT2 and α1 receptors. (R)-roemerine was the most potent compound at 5-HT2A and 5-HT2C receptors (pKb = 7.8-7.9) with good selectivity compared to (S)-roemerine at these two receptors and compared to its activity at 5-HT2B, α1A, α1B and α1D receptors.
