MGS0039: a potent and selective group II metabotropic glutamate receptor antagonist with antidepressant-like activity.

The present study describes the pharmacological profile of (1R,2R,3R,5R,6R)-2-Amino-3-(3,4-dichlorobenzyloxy)-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (MGS0039), a novel group II mGluR antagonist. MGS0039 showed high affinity for both mGluR2 (Ki = 2.2 nM) and mGluR3 (Ki = 4.5 nM), which are comparable to LY341495, another group II mGluR antagonist. MGS0039 attenuated both glutamate-induced inhibition of forskolin-evoked cyclic AMP formation in CHO cells expressing mGluR2 (IC50 = 20 nM) or mGluR3 (IC50 = 24 nM) and glutamate-increased [35S]GTPgammaS binding to mGluR2 (pA2 = 8.2), which means that MGS0039 acts as an antagonist. MGS0039 shifted the dose-response curve of glutamate-increased [35S]GTPgammaS binding rightward without altering the maximal response, and thereby indicating competitive antagonism. MGS0039 showed no significant effects on other mGluRs as well as the other receptors and transporters we studied. MGS0039 (0.3-3 mg/kg, i.p.) as well as LY341495 (0.1-3 mg/kg, i.p.) had dose-dependent antidepressant-like effects in the rat forced swim test and in the mouse tail suspension test. In contrast, MGS0039 (0.3-3 mg/kg, i.p.) had no apparent effect in the rat social interaction test and in the rat elevated plus-maze. These results indicate that MGS0039 is a potent and selective antagonist of group II mGluR, and that group II mGluR antagonists, like MGS0039, have an antidepressant-like potential in experimental animal models.