n-(4-methoxybenzyl)-n--(5-nitro-1-3-thiazol-2-yl)urea and Alzheimer-Disease

Glycogen synthase kinase-3 is a multi-functional serine-threonine kinase and is involved in diverse physiological processes, including metabolism, cell cycle, and gene expression by regulating a wide variety of known substrates like glycogen synthase, tau-protein and β-catenin. Aberrant GSK-3 has been involved in diabetes, inflammation, cancer, Alzheimer's and bipolar disorder. In this review, we present an overview of the involvement of GSK-3 in various signalling pathways, resulting in a number of adverse pathologies due to its dysregulation. In addition, a detailed description of the small molecule inhibitors of GSK-3 with different mode of action discovered or specifically developed for GSK-3 has been presented. Furthermore, some clues for the future optimization of these promising molecules to develop specific drugs inhibiting GSK-3, for the treatment of associated disease conditions have also been discussed.

Topics: Alzheimer Disease; Animals; Bipolar Disorder; Clinical Trials as Topic; Diabetes Mellitus; Drug Discovery; Glycogen Synthase Kinase 3; Humans; Models, Molecular; Neoplasms; Patents as Topic; Phosphorylation; Protein Kinase Inhibitors; Signal Transduction

The natural product harmine, a representative β-carboline alkaloid from the seeds of Peganum harmala L. (Zygophyllaceae), possesses a broad spectrum of biological activities. In this study, a novel series of harmine derivatives containing N-benzylpiperidine moiety were identified for the treatment of Alzheimer's disease (AD). The results showed that all the derivatives possessed significant anti-acetylcholinesterase (AChE) activity and good selectivity over butyrylcholinesterase (BChE). In particular, compound ZLWH-23 exhibited potent anti-AChE activity (IC

Topics: Acetylcholinesterase; Alzheimer Disease; Antineoplastic Agents; Apoptosis; Carbolines; Cell Line, Tumor; Cell Proliferation; Cholinesterase Inhibitors; Drug Design; Glycogen Synthase Kinase 3 beta; Humans; Molecular Docking Simulation; Molecular Dynamics Simulation; Protein Binding; Protein Kinase Inhibitors; Signal Transduction; Structure-Activity Relationship

Glycogen synthase kinase 3 (GSK-3) has become known for its multifactorial involvement in the pathogenesis of Alzheimer's disease. In this study, a benzothiazole- and benzimidazole set of 1-aryl-3-(4-methoxybenzyl)ureas were synthesised as proposed Cys199-targeted covalent inhibitors of GSK-3β, through the incorporation of an electrophilic warhead onto their ring scaffolds. The nitrile-substituted benzimidazolylurea 2b (IC

Topics: Alzheimer Disease; Glycogen Synthase Kinase 3; Humans; Protein Kinase Inhibitors

The relationship between long-term cholinergic dysfunction and risk of developing dementia is poorly understood. Here we used mice with deletion of the vesicular acetylcholine transporter (VAChT) in the forebrain to model cholinergic abnormalities observed in dementia. Whole-genome RNA sequencing of hippocampal samples revealed that cholinergic failure causes changes in RNA metabolism. Remarkably, key transcripts related to Alzheimer's disease are affected. BACE1, for instance, shows abnormal splicing caused by decreased expression of the splicing regulator hnRNPA2/B1. Resulting BACE1 overexpression leads to increased APP processing and accumulation of soluble Aβ1-42. This is accompanied by age-related increases in GSK3 activation, tau hyperphosphorylation, caspase-3 activation, decreased synaptic markers, increased neuronal death, and deteriorating cognition. Pharmacological inhibition of GSK3 hyperactivation reversed deficits in synaptic markers and tau hyperphosphorylation induced by cholinergic dysfunction, indicating a key role for GSK3 in some of these pathological changes. Interestingly, in human brains there was a high correlation between decreased levels of VAChT and hnRNPA2/B1 levels with increased tau hyperphosphorylation. These results suggest that changes in RNA processing caused by cholinergic loss can facilitate Alzheimer's-like pathology in mice, providing a mechanism by which decreased cholinergic tone may increase risk of dementia.

Topics: Acetylcholine; Alzheimer Disease; Amyloid beta-Peptides; Amyloid Precursor Protein Secretases; Animals; Aspartic Acid Endopeptidases; Cells, Cultured; Disease Models, Animal; Embryo, Mammalian; Enzyme Inhibitors; Gene Expression Regulation; Glycogen Synthase Kinase 3; Hippocampus; Humans; Learning Disabilities; Mice; Mice, Inbred C57BL; Mice, Transgenic; RNA; Thiazoles; Thyroid Nuclear Factor 1; Urea; Vesicular Acetylcholine Transport Proteins

Glycogen synthase kinase-3β, also called tau phosphorylating kinase, is a proline-directed serine/threonine kinase which was originally identified due to its role in glycogen metabolism. Active forms of GSK3β localize to pretangle pathology including dystrophic neuritis and neurofibrillary tangles in Alzheimer's disease (AD) brain. By using a high throughput screening (HTS) approach to search for new chemical series and cocrystallization of key analogues to guide the optimization and synthesis of our pyrazine series, we have developed highly potent and selective inhibitors showing cellular efficacy and blood-brain barrier penetrance. The inhibitors are suitable for in vivo efficacy testing and may serve as a new treatment strategy for Alzheimer's disease.

Topics: 3T3 Cells; Alzheimer Disease; Animals; Blood-Brain Barrier; Caco-2 Cells; Cattle; Crystallography, X-Ray; Drug Design; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Humans; Mice; Models, Molecular; Molecular Structure; Permeability; Phosphorylation; Pyrazines; Solubility; Sulfonamides; tau Proteins