Discovery of novel brain permeable and G protein-biased beta-1 adrenergic receptor partial agonists for the treatment of neurocognitive disorders
| Autor: | 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 |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
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 |
| Zdroj: | PLoS ONE PLoS ONE, Vol 12, Iss 7, p e0180319 (2017) |
| ISSN: | 1932-6203 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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