Identification of Glutathione Conjugates of Acetylene- Containing Positive Allosteric Modulators of Metabotropic Glutamate Receptor Subtype
نویسندگان
چکیده
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-Myers Squibb Co., Route 206 & Province Line Road, Princeton, NJ 08543 This article has not been copyedited and formatted. The final version may differ from this version. DMD Fast Forward. Published on January 29, 2015 as DOI: 10.1124/dmd.114.061879
منابع مشابه
Identification 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 کاملIterative experimental and virtual high-throughput screening identifies metabotropic glutamate receptor subtype 4 positive allosteric modulators.
Activation of metabotropic glutamate receptor subtype 4 has been shown to be efficacious in rodent models of Parkinson's disease. Artificial neural networks were trained based on a recently reported high throughput screen which identified 434 positive allosteric modulators of metabotropic glutamate receptor subtype 4 out of a set of approximately 155,000 compounds. A jury system containing thre...
متن کاملDmd061879 578..589
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 کاملProbing the metabotropic glutamate receptor 5 (mGlu₅) positive allosteric modulator (PAM) binding pocket: discovery of point mutations that engender a "molecular switch" in PAM pharmacology.
Positive allosteric modulation of metabotropic glutamate receptor subtype 5 (mGlu₅) is a promising novel approach for the treatment of schizophrenia and cognitive disorders. Allosteric binding sites are topographically distinct from the endogenous ligand (orthosteric) binding site, allowing for co-occupation of a single receptor with the endogenous ligand and an allosteric modulator. Negative a...
متن کاملTetrahydronaphthyridine 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 کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
عنوان ژورنال:
دوره شماره
صفحات -
تاریخ انتشار 2015