Pharmacological and Pharmacokinetic Properties of a Structurally Novel, Potent, and Selective Metabotropic Glutamate 2/3 Receptor Agonist: In Vitro Characterization of

Group II metabotropic glutamate (mGlu) receptor agonists, in-cluding (1S,2S,5R,6S)-2-aminobicyclo[3.1.0]hexane-2,6-dicar-boxylate monohydrate (LY354740) and ()-2-oxa-4-aminobicyclo[3.1.0]hexane-4,6-dicarboxylate (LY379268), have demonstrated efficacy in animal models of anxiety and schizo-phrenia, and LY354740 decreased anxiety in human subjects. Herein, we report the in vitro pharmacological profile and phar-macokinetic properties of another potent, selective, and struc-turally novel mGlu2/3 receptor agonist, ()-(1R,4S,5S,6S)-4-amino-2-sulfonylbicyclo[3.1.0]hexane-4,6-dicarboxylic acid (LY404039) and provide comparisons with LY354740. Similar to LY354740, LY404039 is a nanomolar potent agonist at recom-binant human mGlu2 and mGlu3 receptors (Ki 149 and 92, respectively) and in rat neurons expressing native mGlu2/