RESUMO
'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.
Assuntos
Doença de Alzheimer/metabolismo , Córtex Cerebral/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Glucose/metabolismo , Fármacos Neuroprotetores/uso terapêutico , Transdução de Sinais/genética , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/genética , Peptídeos beta-Amiloides/metabolismo , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/patologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/patologia , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Regulação da Expressão Gênica , Glicogênio Sintase Quinase 3 beta/genética , Glicogênio Sintase Quinase 3 beta/metabolismo , Humanos , Insulina/metabolismo , Resistência à Insulina , Metformina/uso terapêutico , Optogenética/métodos , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Compostos de Sulfonilureia/uso terapêutico , Proteínas tau/genética , Proteínas tau/metabolismoRESUMO
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.
Assuntos
Aporfinas/química , Receptor 5-HT2A de Serotonina/metabolismo , Receptores Adrenérgicos alfa 1/metabolismo , Serotonina/química , Agonistas de Receptores Adrenérgicos alfa 1/química , Agonistas de Receptores Adrenérgicos alfa 1/metabolismo , Aporfinas/metabolismo , Sítios de Ligação , Células HEK293 , Humanos , Cinética , Simulação de Acoplamento Molecular , Estrutura Terciária de Proteína , Receptor 5-HT2A de Serotonina/química , Receptor 5-HT2A de Serotonina/genética , Receptores Adrenérgicos alfa 1/química , Receptores Adrenérgicos alfa 1/genética , Serotonina/metabolismo , Agonistas do Receptor 5-HT2 de Serotonina/química , Agonistas do Receptor 5-HT2 de Serotonina/metabolismo , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
[This corrects the article DOI: 10.1039/C7MD00629B.].
RESUMO
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.