IN VITRO AND IN VIVO PHARMACOLOGICAL PROFILE OF MGS0039, A NOVEL POTENT AND SELECTIVE ANTAGONIST OF GROUP II METABOTROPIC GLUTAMATE RECEPTOR

Glutamatergic abnormalities are involved in several psychiatric disorders. Recent studies suggest group II mGluR has crucial roles in the control of emotional states. We report here pharmacological profile of MGS0039, a newly synthesized group II mGluR antagonist. MGS0039 showed high affinity for both mGluR2 (IC50=2. 2 nM) and mGluR3 (IC50=4. 5nM). MGS0039 attenuated both glutamate-induced inhibition of folskolin-evoked cAMP formation in mGluR2 or 3 expressing cells and glutamate-induced [35S]GTPgS binding to mGluR2, indicating MGS0039 acts as an antagonist. MGS0039 did not show any significant effects on other mGluRs as well as other receptors studied. MGS0039 as well as LY341495 showed dose-dependent antidepressant-like effects in rat forced swim and mouse tail suspension, and dose-dependently reduced marble buried in mice, as did fluvoxamine and buspirone. These data indicate that MGS0039 is a potent and selective antagonist of group II mGluR, and that MGS0039 may have antidepressant-and anxiolytic-like potential in experimental animal models.