Synthesis and Pharmacological Characterization of C4-(Thiotriazolyl)-substituted-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylates. Identification of (1R,2S,4R,5R,6R)-2-Amino-4-(1H-1,2,4-triazol-3-ylsulfanyl)bicyclo[3.1.0]hexane-2,6-dicarboxylic Acid (LY2812223), a Highly Potent, Functionally Selective mGlu2 Receptor Agonist

Identification of orthosteric mGlu(2/3) receptor agonists capable of discriminating between individual mGlu(2) and mGlu(3) subtypes has been highly challenging owing to the glutamate-site sequence homology between these proteins. Herein we detail the preparation and characterization of a series of molecules related to (1S,2S,5R,65)-2-aminobicyclo [3.1.0]hexane-2,6-dicarboxylate 1 (LY354740) bearing C4-thiotriazole substituents. On the basis of second messenger responses in cells expressing other recombinant human mGlu(2/3) subtypes, a number of high potency and efficacy mGlu(2) receptor agonists exhibiting low potency mGlu(3) partial agonist/antagonist activity were identified. From this, (1R,2S,4R,512,6R)-2-amino-4-(1H-1,2,4-triazol-3-ylsulfanyl)bicydo[3.1.0]hexane-2,6-dicarboxylic acid 14a (LY2812223) was further characterized. Cocrystallization of 14a with the amino terminal domains of hmGlu(2) and hmGlu(3) combined with site-directed mutation studies has clarified the underlying molecular basis of this unique pharmacology. Evaluation of 14a in a rat model responsive to mGlu(2) receptor activation coupled with a measure of central drug disposition provides evidence that this molecule engages and activates central mGlu(2) receptors in vivo.