Synthesis and Pharmacological
Characterization of
C4-Disubstituted Analogs of 1<i>S</i>,2<i>S</i>,5<i>R</i>,6<i>S</i>‑2-Aminobicyclo[3.1.0]hexane-2,6-dicarboxylate:
Identification of a Potent, Selective Metabotropic Glutamate Receptor
Agonist and Determination of Agonist-Bound Human mGlu2 and mGlu3 Amino
Terminal Domain Structures
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Abstract
As part of our ongoing research to
identify novel agents acting
at metabotropic glutamate 2 (mGlu2) and 3 (mGlu3) receptors, we have
previously reported the identification of the C4<sub>α</sub>-methyl analog of mGlu2/3 receptor agonist <b>1</b> (LY354740).
This molecule, 1<i>S</i>,2<i>S</i>,4<i>R</i>,5<i>R</i>,6<i>S</i>-2-amino-4-methylbicyclo[3.1.0]hexane-2,6-dicarboxylate <b>2</b> (LY541850), exhibited an unexpected mGlu2 agonist/mGlu3
antagonist pharmacological profile, whereas the C4<sub>β</sub>-methyl diastereomer (<b>3</b>) possessed dual mGlu2/3 receptor
agonist activity. We have now further explored this structure–activity
relationship through the preparation of cyclic and acyclic C4-disubstituted
analogs of <b>1</b>, leading to the identification of C4-spirocyclopropane <b>5</b> (LY2934747), a novel, potent, and systemically bioavailable
mGlu2/3 receptor agonist which exhibits both antipsychotic and analgesic
properties in vivo. In addition, through the combined use of protein–ligand
X-ray crystallography employing recombinant human mGlu2/3 receptor
amino terminal domains, molecular modeling, and site-directed mutagenesis,
a molecular basis for the observed pharmacological profile of compound <b>2</b> is proposed