LY-2794193

Analogs based on the 2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylate scaffold showed high potency and selectivity as both group II mGlu receptors orthosteric agonists and antagonists. This scaffold was initially designed to mimic the fully extended glutamate backbone conformation that was hypothesized to be the active conformation for the group II mGlu receptors. With the availability of crystal structures of l-Glu-bound amino terminal domain proteins from multiple mGlu receptor subtypes spanning all three subgroups, a new steric hindrance hypothesis was proposed to account for the scaffold's unique group II selectivity that explores the subtle distance differences between the α-carbon of l-Glu and the center of the tyrosine phenyl ring from the bottom lobe (e.g. Y216 of mGlu₂).