LY354740 is a Potent and Highly Selective Group II Metabotropic Glutamate Receptor Agonist in Cells Expressing Human Glutamate Receptors
Section snippets
Second messenger assays in cloned human mGlu receptors
Cloned human mGlu receptors mGlu1a, mGlu2, mGlu3, mGlu4a, mGlu5a and mGlu7 were each expressed in “RGT” cells. RGT cells are AV12-664 cells (American Type Culture Collection, accession number CRL 9595) which have been stably transfected with a glutamate transporter (GLAST, Storck et al., 1992) to prevent the accumulation of glutamate into the cell media (Desai et al., 1995; Kingston et al., 1995; Schoepp et al., 1996). RGT cells expressing human mGlu receptors were seeded into 24-well culture
Activity of LY354740 at cAMP coupled human mGlu receptors
As shown in Fig. 2, LY354740 most potently inhibited forskolin-stimulated cAMP formation in cells expressing human mGlu2 receptors, producing >90% inhibition at a maximally effective concentration of 100 nM and an ec50 value of 5.1 ± 0.3 nM. LY354740 was also a full-agonist at the human mGluR3 receptor, but was about six-fold less potent than when compared to the human mGlu2 receptor (see Table 1). No appreciable agonist activity (<50% inhibition of forskolin-stimulated cAMP) was noted at group
DISCUSSION
The relatively recent cloning of a highly heterogeneous family of G-protein coupled (metabotropic) receptors has created a tremendous gap between the knowledge of the mGlu receptor subtypes versus an understanding about their cellular functions. The discovery of potent subtype selective mGlu receptor compounds is needed to further explore mGlu receptor functions and the therapeutic opportunities that may arise from selective modulation of these receptors. The availability of cell lines
Acknowledgements
We would like to thank Allelix Biopharmaceuticals for providing the human GluR4- and GluR6-expressing cells.
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2017, Journal of Chromatography B: Analytical Technologies in the Biomedical and Life SciencesCitation Excerpt :LY-354,740 (1S,2S,5R,6S)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid, also referred to as eglumegad, is a conformationally constrained analogue of glutamic acid (Fig. 1). LY-354,740 is a potent and selective orthosteric agonist of the group II metabotropic glutamate receptors (mGluR), with selectivity for mGluR2 over mGluR3 [1], and without significant affinity for the other mGluR or ionotropic glutamate receptors [2]. Several studies have indicated that agonists of mGluR2, such as LY-354,740, may be useful in the treatment of many psychiatric disorders, including psychosis, anxiety, and drug withdrawal [3–9].