Exploration of Allosteric Agonism Structure–Activity Relationships within an Acetylene Series of Metabotropic Glutamate Receptor 5 (mGlu5) Positive Allosteric Modulators (PAMs): Discovery of 5-((3-Fluorophenyl)ethynyl)-N-(3-methyloxetan-3-yl)picolinamide (ML254)
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چکیده
منابع مشابه
Tetrahydronaphthyridine and Dihydronaphthyridinone Ethers As Positive Allosteric Modulators of the Metabotropic Glutamate Receptor 5 (mGlu5)
Positive allosteric modulators (PAMs) of metabotropic glutamate receptor 5 (mGlu5) represent a promising therapeutic strategy for the treatment of schizophrenia. Starting from an acetylene-based lead from high throughput screening, an evolved bicyclic dihydronaphthyridinone was identified. We describe further refinements leading to both dihydronaphthyridinone and tetrahydronaphthyridine mGlu5 P...
متن کاملIdentification of glutathione conjugates of acetylene-containing positive allosteric modulators of metabotropic glutamate receptor subtype 5.
A recent medicinal chemistry campaign to identify positive allosteric modulators (PAMs) of metabotropic glutamate receptor subtype 5 (mGluR5) led to the discovery of potent compounds featuring an oxazolidinone structural core flanked by biaryl acetylene and haloaryl moieties. However, biotransformation studies of some of these mGluR5 PAMs demonstrated the formation of glutathione (GSH) conjugat...
متن کاملIdentification of Glutathione Conjugates of Acetylene- Containing Positive Allosteric Modulators of Metabotropic Glutamate Receptor Subtype
XIAOLIANG ZHUO, XIAOHUA STELLA HUANG, ANDREW P. DEGNAN, LAWRENCE B. SNYDER, FUKANG YANG, HONG HUANG, YUE-ZHONG SHU, BENJAMIN M. JOHNSON Department of Biotransformation (X.Z., B.M.J.), Discovery Analytical Sciences (X.S.H.), Neuroscience Chemistry (A.P.D., L.B.S., F.Y., H.H.), Bristol-Myers Squibb Co., 5 Research Parkway, Wallingford, CT 06492 Department of Biotransformation (Y.-Z.S.), Bristol-M...
متن کاملMetabotropic glutamate receptor 5 positive allosteric modulators are neuroprotective in a mouse model of Huntington's disease
BACKGROUND AND PURPOSE Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by a polyglutamine expansion in the huntingtin protein. We have previously demonstrated that the cell signalling of the metabotropic glutamate receptor 5 (mGluR5) is altered in a mouse model of HD. Although mGluR5-dependent protective pathways are more activated in HD neurons, intracellul...
متن کاملPositive allosteric modulators of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor.
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ژورنال
عنوان ژورنال: Journal of Medicinal Chemistry
سال: 2013
ISSN: 0022-2623,1520-4804
DOI: 10.1021/jm401028t