A Novel Compound Of Pyrrolidone Derivatives As A M1 Muscarinic Acetylcholine Receptor Agonist And Its Application To Alzheimer?s Disease | 12494
Journal of Alzheimers Disease & Parkinsonism
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Muscarinic acetylcholine receptors (mAChRs) are widely expressed in the central nervous system (CNS) and modulate
multiple neuronal functions. The predominant type of mAChRs in the CNS is the M1 subtype, and M1 mAChR is located
in the cerebral cortex and hippocampus. Both of these brain areas are known to be important for cognition, learning and memory
and to develop amyloid plaques in Alzheimer?s disease. Based on these observations, it has been suggested that the M1 mAChR
has long been viewed as a potential therapeutic target for the treatment of Alzheimer?s disease and other CNS disorders.
Herein, we described the synthesis of pyrrolidone derivatives and assayed them against all five subtypes (M1 - M5) of
mAchRs. Using an FDSS6000 96-well fluorescence plate reader, we assayed 18 pyrrolidone derivative compounds in HEK293 cells
transiently transfected with each human mAchR. In the presence study, we found compound KK1259 is a potent and selective
agonist of M1 mAchR. Furthermore, we examined the effect of compound KK1259 on extracellular signal-regulated kinase 1/2
(ERK1/2) phosphorylation and a computational mapping of compound KK1259 into 6-feature 3D pharmacophore hypothesis to
acquire more information about structure-activity relationships.
Hyewhon Rhim has completed her Ph.D. at the age of 33 years from the University of Chicago and postdoctoral studies from the University of
Chicago and Seoul National University. She is a Principal Research Scientist, Center for Neuroscience, Brain Science Institute Korea Institute of
Science and Technology in Seoul, Korea. She has published more than 130 papers in reputed journals and 50 domestic and international patents.
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