Discovery of novel brain permeable and G protein-biased beta-1 adrenergic receptor partial agonists for the treatment of neurocognitive disorders
| العنوان: | Discovery of novel brain permeable and G protein-biased beta-1 adrenergic receptor partial agonists for the treatment of neurocognitive disorders |
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| المؤلفون: | Vijay S. Pande, Bitna Yi, Mehrdad Shamloo, Michael F. Green, Jacqueline Ernest, Evan N. Feinberg, Andrew K. Evans, Denise I. Briggs, Kristine Ravina, Amir Barati Farimani, Wenchao Sun, Alam Jahangir, Jayakumar Rajadas |
| المصدر: | PLoS ONE PLoS ONE, Vol 12, Iss 7, p e0180319 (2017) |
| سنة النشر: | 2017 |
| مصطلحات موضوعية: | 0301 basic medicine, Male, Models, Molecular, Central Nervous System, Partial Agonists, Cell signaling, Magnetic Resonance Spectroscopy, lcsh:Medicine, Pharmacology, Signal transduction, Crystallography, X-Ray, Nervous System, Beta-1 adrenergic receptor, Propanolamines, Rats, Sprague-Dawley, 0302 clinical medicine, Cricetinae, Drug Discovery, Medicine and Health Sciences, Receptor, lcsh:Science, Cells, Cultured, Multidisciplinary, Molecular Structure, Chemistry, Phenyl Ethers, Brain, Drugs, Signaling cascades, Neurodegenerative Diseases, cAMP signaling cascade, Neurology, Adrenergic beta-1 Receptor Agonists, Physical Sciences, Anatomy, Protein Binding, Research Article, Agonist, Cell biology, Adrenergic receptor, G protein, medicine.drug_class, Neurocognitive Disorders, CHO Cells, Partial agonist, Neuroprotection, Permeability, 03 medical and health sciences, Structure-Activity Relationship, Cricetulus, Phenols, Alzheimer Disease, GTP-Binding Proteins, Cell Line, Tumor, Microsomes, Mental Health and Psychiatry, medicine, Animals, Humans, lcsh:R, Isoproterenol, Chemical Compounds, Biology and Life Sciences, Mice, Inbred C57BL, G-Protein Signaling, 030104 developmental biology, Models, Chemical, lcsh:Q, Dementia, Receptors, Adrenergic, beta-1, 030217 neurology & neurosurgery |
| الوصف: | The beta-1 adrenergic receptor (ADRB1) is a promising therapeutic target intrinsically involved in the cognitive deficits and pathological features associated with Alzheimer's disease (AD). Evidence indicates that ADRB1 plays an important role in regulating neuroinflammatory processes, and activation of ADRB1 may produce neuroprotective effects in neuroinflammatory diseases. Novel small molecule modulators of ADRB1, engineered to be highly brain permeable and functionally selective for the G protein with partial agonistic activity, could have tremendous value both as pharmacological tools and potential lead molecules for further preclinical development. The present study describes our ongoing efforts toward the discovery of functionally selective partial agonists of ADRB1 that have potential therapeutic value for AD and neuroinflammatory disorders, which has led to the identification of the molecule STD-101-D1. As a functionally selective agonist of ADRB1, STD-101-D1 produces partial agonistic activity on G protein signaling with an EC50 value in the low nanomolar range, but engages very little beta-arrestin recruitment compared to the unbiased agonist isoproterenol. STD-101-D1 also inhibits the tumor necrosis factor α (TNFα) response induced by lipopolysaccharide (LPS) both in vitro and in vivo, and shows high brain penetration. Other than the therapeutic role, this newly identified, functionally selective, partial agonist of ADRB1 is an invaluable research tool to study mechanisms of G protein-coupled receptor signal transduction. |
| تدمد: | 1932-6203 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::bef584b2f58cefd45336892b625170d3 https://pubmed.ncbi.nlm.nih.gov/28746336 |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....bef584b2f58cefd45336892b625170d3 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 19326203 |
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