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Absence of direct effects on the dopamine D2 receptor by mGluR2/3‐selective receptor agonists LY 354,740 and LY 379,268
Author(s) -
Zysk John R.,
Widzowski Dan,
Sygowski Linda A.,
Knappenberger Katharine S.,
Spear Nathan,
Elmore Charles S.,
Dorff Peter,
Liu Hongyan,
Doherty James,
Chhajlani Vijay
Publication year - 2011
Publication title -
synapse
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.809
H-Index - 106
eISSN - 1098-2396
pISSN - 0887-4476
DOI - 10.1002/syn.20817
Subject(s) - chemistry , agonist , raclopride , receptor , metabotropic receptor , domperidone , pharmacology , dopamine receptor d2 , dopamine , biophysics , endocrinology , biochemistry , biology
We previously reported the absence of high‐affinity binding of the group II metabotropic glutamate receptor agonists LY 354,740 and LY 379,268 to the D2L dopamine receptor. A rebuttal to our findings has since been reported (see Introduction section); this study represents our response. Analysis by LCMS of LY 354,740 and LY 379,268 used in this study revealed the correct molecular mass for these compounds. Both LY 354,740 and LY 379,268 exhibited potent agonist activity for mGluR 2 in the 35 S‐GTPγS assay. Functionally, neither compound displayed antagonist activity in the GTPγS assay with recombinant D 2 . At concentrations up to 10 μM, both compounds failed to displace [ 3 H]‐raclopride, [ 3 H]‐PHNO, or [ 3 H]‐domperidone in filter‐binding assays under isotonic (120 mM NaCl or N ‐methyl glucamine) or low‐ionic strength (no NaCl or N ‐methyl glucamine) conditions. Some displacement of [ 3 H]‐domperidone (20–40%) was observed at 30 μM of LY 354,740 under low‐ionic strength and under isotonic conditions in the absence of NaCl. No displacement of [ 3 H]‐domperidone was detected in a two site model at lower (<100 nM) concentrations of either compound. Moreover, no D 2 activity was observed for LY 354,740 or LY 379,268 in the CellKey™ (cellular dielectric spectroscopy) assay. In this communication, we discuss the possible reasons for differences in our study and the previously published work and implications of these studies for mechanisms of antipsychotic action. Synapse 65:64–68, 2011. © 2010 Wiley‐Liss, Inc.