Niswender, Colleen M. published the artcileContext-dependent pharmacology exhibited by negative allosteric modulators of metabotropic glutamate receptor, COA of Formula: C11H7ClFNO3, the publication is Molecular Pharmacology (2010), 77(3), 459-468, database is CAplus and MEDLINE.
Phenotypic studies of mice lacking metabotropic glutamate receptor subtype 7 (mGluR7) suggest that antagonists of this receptor may be promising for the treatment of central nervous system disorders such as anxiety and depression. Suzuki et al. recently reported the in vitro characterization of a novel mGluR7 antagonist called 6-(4-methoxyphenyl)-5-methyl-3-(4-pyridinyl)-isoxazolo[4,5-c]pyridin-4(5H)-one (MMPIP), which noncompetitively inhibited the activity of orthosteric and allosteric agonists at mGluR7. We describe that MMPIP acts as a noncompetitive antagonist in calcium mobilization assays in cells coexpressing mGluR7 and the promiscuous G protein Gα15. Assessment of the activity of a small library of MMPIP-derived compounds using this assay reveals that, despite similar potencies, compounds exhibit differences in neg. cooperativity for agonist-mediated calcium mobilization. Examination of the inhibitory activity of MMPIP and analogs using endogenous Gi/o-coupled assay readouts indicates that the pharmacol. of these ligands seems to be context-dependent, and MMPIP exhibits differences in neg. cooperativity in certain cellular backgrounds. Electrophysiol. studies reveal that, in contrast to the orthosteric antagonist (2S)-2-amino-2-[(1S,2S)-2-carboxyclycloprop-1-yl]-3-(xanth-9-yl) propanoic acid (LY341495), MMPIP is unable to block agonist-mediated responses at the Schaffer collateral-CA1 synapse, a location at which neurotransmission has been shown to be modulated by mGluR7 activity. Thus, MMPIP and related compounds differentially inhibit coupling of mGluR7 in different cellular backgrounds and may not antagonize the coupling of this receptor to native Gi/o signaling pathways in all cellular contexts. The pharmacol. of this compound represents a striking example of the potential for context-dependent blockade of receptor responses by neg. allosteric modulators.
Molecular Pharmacology published new progress about 3919-74-2. 3919-74-2 belongs to chlorides-buliding-blocks, auxiliary class Isoxazole,Fluoride,Chloride,Carboxylic acid,Benzene, name is 3-(2-Chloro-6-fluorophenyl)-5-methylisoxazole-4-carboxylic acid, and the molecular formula is C11H7ClFNO3, COA of Formula: C11H7ClFNO3.
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