Metabotropic glutamate 2/3 receptors (mGlu2/3R) are members of the class C G-protein coupled receptor family. These receptors are highly expressed in forebrain regions (e.g. cortex, hippocampus, striatum & amygdala) where they act to regulate neuronal excitability. Negative modulators of mGlu 2/3 receptors demonstrate antidepressant-like activity in animal models and hold promise as novel therapeutic agents for the treatment of major depressive disorder. This poster will describe efforts to prepare and optimize a series of conformationally constrained 3,4-disubstituted bicyclo[3.1.0]hexane glutamic acid analogs as orthosteric (glutamate site) mGlu2/3R antagonists. This work led to the discovery of a highly potent and efficacious tool compound 1  (mGluR2 IC50 43.3 nM (� 14.2, n = 6), mGluR3 IC50= 27.2 nM (� 9.33, n = 5)) that exhibited wake promoting and antidepressant-like properties in rodents.

Discovery of novel bicyclo[3.1.0]hexane analogs as antagonists of metabotropic glutamate 2/3 receptors for the treatment of depression

248th National Meeting (2014)

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