Tarr, James C. published the artcileTargeting Selective Activation of M1 for the Treatment of Alzheimer’s Disease: Further Chemical Optimization and Pharmacological Characterization of the M1 Positive Allosteric Modulator ML169, Computed Properties of 763120-58-7, the publication is ACS Chemical Neuroscience (2012), 3(11), 884-895, database is CAplus and MEDLINE.
The M1 muscarinic acetylcholine receptor is thought to play an important role in memory and cognition, making it a potential target for the treatment of Alzheimer’s disease (AD) and schizophrenia. Moreover, M1 interacts with BACE1 and regulates its proteasomal degradation, suggesting selective M1 activation could afford both palliative cognitive benefit as well as disease modification in AD. A key challenge in targeting the muscarinic acetylcholine receptors is achieving mAChR subtype selectivity. Our lab has previously reported the M1 selective pos. allosteric modulator ML169. Herein we describe our efforts to further optimize this lead compound by preparing analog libraries and probing novel scaffolds. We were able to identify several analogs that possessed submicromolar potency, with our best example displaying an EC50 of 310 nM. The new compounds maintained complete selectivity for the M1 receptor over the other subtypes (M2-M5), displayed improved DMPK profiles, and potentiated the carbachol (CCh)-induced excitation in striatal MSNs. Selected analogs were able to potentiate CCh-mediated non-amyloidogenic APPα release, further strengthening the concept that M1 PAMs may afford a disease-modifying role in the treatment of AD.
ACS Chemical Neuroscience published new progress about 763120-58-7. 763120-58-7 belongs to pyrazoles-derivatives, auxiliary class Pyrazole,Boronic acid and ester,Boronic Acids,Boronic acid and ester, name is 1H-Pyrazole-4-boronic acid, and the molecular formula is C9H5ClO2, Computed Properties of 763120-58-7.
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