Further Information:
Corresponding author: Vijay.Chhajlani@astrazeneca.com
Absence of direct effects on the dopamine D2 receptor by mGluR2/3-selective receptor agonists LY 354,740 and LY 379,268.
Synapse (New York, N.Y.) 2010 May 19; In press
Zysk J JR, Widzowski D, Sygowski L LA, Knappenberger K KS, Spear N, Elmore C CS, Dorff P, Liu H, Doherty J, Chhajlani V
Neuroscience, AstraZeneca Pharmaceuticals.
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); the present 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-GTPgammaS assay. Functionally, neither compound displayed antagonist activity in the GTPgammaS assay with recombinant D(2). At concentrations up to 10 muM, 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 muM 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, 2010. (c) 2010 Wiley-Liss, Inc.