Design and Synthesis of Neuroprotective Methylthiazoles and Modification as NO-Chimeras for Neurodegenerative Therapy
| Autor: | Ehsan Tavassoli, Jia Luo, Zhihui Qin, Ottavio Arancio, Lawren VandeVrede, Gregory R. J. Thatcher, Mauro Fa, Andrew F. Teich |
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| Rok vydání: | 2012 |
| Předmět: |
Male
Transgene Primary Cell Culture Excitotoxicity Hippocampus Biological Availability Mice Transgenic Pharmacology Biology Neurotransmission medicine.disease_cause Nitric Oxide Neuroprotection Synaptic Transmission Article Small Molecule Libraries Therapeutic approach Amyloid beta-Protein Precursor Mice Structure-Activity Relationship Alzheimer Disease Drug Discovery medicine Avoidance Learning Pathology Animals Humans Prodrugs Tissue Distribution Neurons FOS: Clinical medicine Molecular Mimicry Neurosciences Brain Drugs medicine.disease Receptors GABA-A Mice Inbred C57BL Oxygen Thiazoles Glucose Neuroprotective Agents Mutation Molecular Medicine Click Chemistry Alzheimer's disease Cognition Disorders Oxidative stress |
| DOI: | 10.7916/d8154f4r |
| Popis: | Learning and memory deficits in Alzheimer’s disease (AD) result from synaptic failure and neuronal loss, the latter caused in part by excitotoxicity and oxidative stress. A therapeutic approach is described, which uses NO-chimeras directed at restoration of both synaptic function and neuroprotection. 4-Methylthiazole (MZ) derivatives were synthesized, based upon a lead neuroprotective pharmacophore acting in part by GABAA receptor potentiation. MZ derivatives were assayed for protection of primary neurons against oxygen-glucose deprivation and excitotoxicity. Selected neuroprotective derivatives were incorporated into NO-chimera prodrugs, coined nomethiazoles. To provide proof of concept for the nomethiazole drug class, selected examples were assayed for: restoration of synaptic function in hippocampal slices from AD-transgenic mice; reversal of cognitive deficits; and, brain bioavailability of the prodrug and its neuroprotective MZ metabolite. Taken together the assay data suggest that these chimeric nomethiazoles may be of use in treatment of multiple components of neurodegenerative disorders, such as AD. |
| Databáze: | OpenAIRE |
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