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1.
Int J Mol Sci ; 25(17)2024 Aug 29.
Artículo en Inglés | MEDLINE | ID: mdl-39273333

RESUMEN

We previously found that chronic adenosine A1 receptor stimulation with N6-Cyclopentyladenosine increased α-synuclein misfolding and neurodegeneration in a novel α-synucleinopathy model, a hallmark of Parkinson's disease. Here, we aimed to synthesize a dimer caffeine-indan linked by a 6-carbon chain to cross the blood-brain barrier and tested its ability to bind α-synuclein, reducing misfolding, behavioral abnormalities, and neurodegeneration in our rodent model. Behavioral tests and histological stains assessed neuroprotective effects of the dimer compound. A rapid synthesis of the 18F-labeled analogue enabled Positron Emission Tomography and Computed Tomography imaging for biodistribution measurement. Molecular docking analysis showed that the dimer binds to α-synuclein N- and C-termini and the non-amyloid-ß-component (NAC) domain, similar to 1-aminoindan, and this binding promotes a neuroprotective α-synuclein "loop" conformation. The dimer also binds to the orthosteric binding site for adenosine within the adenosine A1 receptor. Immunohistochemistry and confocal imaging showed the dimer abolished α-synuclein upregulation and aggregation in the substantia nigra and hippocampus, and the dimer mitigated cognitive deficits, anxiety, despair, and motor abnormalities. The 18F-labeled dimer remained stable post-injection and distributed in various organs, notably in the brain, suggesting its potential as a Positron Emission Tomography tracer for α-synuclein and adenosine A1 receptor in Parkinson's disease therapy.


Asunto(s)
Cafeína , Receptor de Adenosina A1 , alfa-Sinucleína , alfa-Sinucleína/metabolismo , Animales , Receptor de Adenosina A1/metabolismo , Cafeína/farmacología , Pliegue de Proteína/efectos de los fármacos , Masculino , Ratas , Fármacos Neuroprotectores/farmacología , Simulación del Acoplamiento Molecular , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/patología , Tomografía de Emisión de Positrones/métodos , Conducta Animal/efectos de los fármacos
2.
Mol Pharm ; 20(2): 853-874, 2023 02 06.
Artículo en Inglés | MEDLINE | ID: mdl-36696533

RESUMEN

Small-molecule drugs have been employed for years as therapeutics in the pharmaceutical industry. However, small-molecule drugs typically have short in vivo half-lives which is one of the largest impediments to the success of many potentially valuable pharmacologically active small molecules. The undesirable pharmacokinetics and pharmacology associated with some small molecules have led to the development of a new class of bioconjugates known as chemically programmed antibodies (cPAbs). cPAbs are bioconjugates in which antibodies are used to augment small molecules with effector functions and prolonged pharmacokinetic profiles, where the pharmacophore of the small molecule is harnessed for target binding and therefore biological targeting. Many different small molecules can be conjugated to large proteins such as full monoclonal antibodies (IgG), fragment crystallizable regions (Fc), or fragment antigen binding regions (Fab). In order to successfully and site-specifically conjugate small molecules to any class of antibodies (IgG, Fc, or Fab), the molecules must be derivatized with a functional group for ease of conjugation without altering the pharmacology of the small molecules. In this Review, we summarize the different synthetic or biological methods that have been employed to produce cPAbs. These unique chemistries have potential to be applied to other fields of antibody modification such as antibody drug conjugates, radioimmunoconjugates, and fluorophore-tagged antibodies.


Asunto(s)
Anticuerpos Monoclonales , Inmunoconjugados , Anticuerpos Monoclonales/química , Inmunoconjugados/química , Antígenos , Inmunoglobulina G/química
3.
Xenobiotica ; 52(8): 811-827, 2022 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-36048000

RESUMEN

Although liquid chromatography-tandem mass spectrometry is the gold standard analytical platform for the quantification of drugs, metabolites, and biomarkers in biological samples, it cannot localise them in target tissues.The localisation and quantification of drugs and/or their associated metabolites in target tissues is a more direct measure of local drug exposure, biodistribution, efficacy, and regional toxicity compared to the traditional substitute studies using plasma.Therefore, combining high spatial resolution imaging functionality with the superior selectivity and sensitivity of mass spectrometry into one analytical technique will be a valuable tool for targeted localisation and quantification of drugs, metabolites, and biomarkers in tissues.Mass spectrometry imaging (MSI) is a tagless analytical technique that allows for the direct localisation and quantification of drugs, metabolites, and biomarkers in biological tissues, and has been used extensively in pharmaceutical research.The overall goal of this current review is to provide a detailed description of the working principle of MSI and its application in pharmacokinetic studies encompassing absorption, distribution, metabolism, excretion, and toxicity processes, followed by a discussion of the strategies for addressing the challenges associated with the functional utility of MSI in pharmacokinetic studies that support drug development.


Asunto(s)
Espectrometría de Masas en Tándem , Distribución Tisular , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción/métodos , Cromatografía Liquida/métodos , Espectrometría de Masas en Tándem/métodos
4.
Xenobiotica ; 52(8): 916-927, 2022 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-36282181

RESUMEN

Aggregates of the protein α-synuclein are associated with pathophysiology of Parkinson's disease and are present in Lewy Bodies found in the brains of Parkinson's patients. We previously demonstrated that bifunctional compounds composed of caffeine linked via a six carbon chain to either 1-aminoindan (C8-6-I) or nicotine (C8-6-N) bind α-synuclein and protect yeast cells from α-synuclein mediated toxicity.A critical step in development of positron emission tomography (PET) probes for neurodegenerative diseases is evaluation of their metabolic stability. We determined that C8-6-I, and C8-6-N both undergo phase 1 P450 metabolism in mouse, rat, and human liver microsomes. We utilised this metabolic information to guide the design of fluorinated analogues for use as PET probes and determined that the fluorine in 19F-C8-6-I and 19F-C8-6-N is stable to P450 enzymes.We have developed and validated an analytical HPLC-UV method following FDA and EMA guidelines to measure in vitro phase 1 kinetics of these compounds and determine their Vmax, KM and CLint,u in mouse liver microsomes. We found that C8-6-I and 19F-C8-6-I have a two- to fourfold lower CLint,u than C8-6-N, and 19F-C8-6-N. Our approach shows a simple, specific, and effective system to design and develop compounds as PET probes.


Asunto(s)
Enfermedad de Parkinson , alfa-Sinucleína , Animales , Humanos , Ratones , Ratas , alfa-Sinucleína/química , alfa-Sinucleína/metabolismo , Cromatografía Líquida de Alta Presión , Cinética , Cuerpos de Lewy/metabolismo , Enfermedad de Parkinson/metabolismo
5.
Xenobiotica ; 51(8): 885-900, 2021 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-34187286

RESUMEN

A challenge in the development of novel 18F-labelled positron emission tomography (PET) imaging probes is identification of metabolically stable sites to incorporate the 18F radioisotope. Metabolic loss of 18F from PET probes in vivo can lead to misleading biodistribution data as displaced 18F can accumulate in various tissues.In this study we report on in vitro hepatic microsomal metabolism of novel caffeine containing bifunctional compounds (C8-6-I, C8-6-N, C8-6-C8) that can prevent in vitro aggregation of α-synuclein, which is associated with the pathophysiology of Parkinson's disease. The metabolic profile obtained guided us to synthesize stable isotope 19F-labelled analogues in which the fluorine was introduced at the metabolically stable N7 of the caffeine moiety.An in vitro hepatic microsomal metabolism study of the 19F-labelled analogues resulted in similar metabolites to the unlabelled compounds and demonstrated that the fluorine was metabolically stable, suggesting that these analogues are appropriate PET imaging probes. This straightforward in vitro strategy is valuable for avoiding costly stability failures when designing radiolabelled compounds for PET imaging.


Asunto(s)
Radioisótopos de Flúor , alfa-Sinucleína , Tomografía de Emisión de Positrones , Distribución Tisular
6.
J Neurol ; 269(11): 5762-5786, 2022 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-35831620

RESUMEN

The development of disease-modifying drugs and differential diagnostic agents is an urgent medical need in Parkinson's disease. Despite the complex pathophysiological pathway, the misfolding of alpha-synuclein has been identified as a putative biomarker for detecting the onset and progression of the neurodegeneration associated with Parkinson's disease. Identifying the most appropriate alpha-synuclein-based diagnostic modality with clinical translation will revolutionize the diagnosis of Parkinson's. Likewise, molecules that target alpha-synuclein could alter the disease pathway that leads to Parkinson's and may serve as first-in class therapeutics compared to existing treatment options such as levodopa and dopamine agonist that do not necessarily modify the disease pathway. Notwithstanding the promising benefits that alpha-synuclein presents to therapeutics and diagnostics development for Parkinson's disease, finding ways to address potential challenges such as inadequate preclinical models, safety and efficacy will be paramount to achieving clinical translation. In this comprehensive review paper, we described the role of alpha-synuclein in the pathogenesis of Parkinson's disease, as well as how its structure and function relationship delineate disease onset and progression. We further discussed different alpha-synuclein-based diagnostic modalities including biomolecular assays and molecular imaging. Finally, we presented current small molecules and biologics that are being developed as disease-modifying drugs or positron emission tomography imaging probes for Parkinson's disease.


Asunto(s)
Productos Biológicos , Enfermedad de Parkinson , Biomarcadores , Agonistas de Dopamina , Humanos , Levodopa , Enfermedad de Parkinson/diagnóstico por imagen , Enfermedad de Parkinson/tratamiento farmacológico , alfa-Sinucleína/metabolismo
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