New 4‑Functionalized Glutamate Analogues Are Selective Agonists at Metabotropic Glutamate Receptor Subtype 2 or Selective Agonists at Metabotropic Glutamate Receptor Group III

The metabotropic glutamate (Glu) receptors (mGluRs) play key roles
in modulating excitatory neurotransmission in the brain. In all, eight
subtypes have been identified and divided into three groups, group
I (mGlu1,5), group II (mGlu2,3), and group III (mGlu4,6–8).
In this article, we present a L-2,4-syn-substituted Glu analogue, 1d, which displays selective agonist activity at mGlu2 over
the remaining mGluR subtypes. A modeling study and redesign of the
core scaffold led to the stereoselective synthesis of four new conformationally
restricted Glu analogues, 2a–d. Most
interestingly, 2a retained a selective agonist activity
profile at mGlu2 (EC50 in the micromolar range), whereas 2c/2d were both selective agonists at group III,
subtypes mGlu4,6,8. In general, 2d was 20-fold more potent
than 2c and potently activated mGlu4,6,8 in the low–mid
nanomolar range.