2 research outputs found
Synthesis and Pharmacological Characterization of <i>C</i>4‑(Thiotriazolyl)-substituted-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylates. Identification of (1<i>R</i>,2<i>S</i>,4<i>R</i>,5<i>R</i>,6<i>R</i>)‑2-Amino-4-(1<i>H</i>‑1,2,4-triazol-3-ylsulfanyl)bicyclo[3.1.0]hexane-2,6-dicarboxylic Acid (LY2812223), a Highly Potent, Functionally Selective mGlu<sub>2</sub> Receptor Agonist
Identification
of orthosteric mGlu<sub>2/3</sub> receptor agonists
capable of discriminating between individual mGlu<sub>2</sub> and
mGlu<sub>3</sub> 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 (1<i>S</i>,2<i>S</i>,5<i>R</i>,6<i>S</i>)-2-aminobicycloÂ[3.1.0]Âhexane-2,6-dicarboxylate <b>1</b> (LY354740) bearing <i>C</i>4-thiotriazole substituents.
On the basis of second messenger responses in cells expressing other
recombinant human mGlu<sub>2/3</sub> subtypes, a number of high potency
and efficacy mGlu<sub>2</sub> receptor agonists exhibiting low potency
mGlu<sub>3</sub> partial agonist/antagonist activity were identified.
From this, (1<i>R</i>,2<i>S</i>,4<i>R</i>,5<i>R</i>,6<i>R</i>)-2-amino-4-(1<i>H</i>-1,2,4-triazol-3-ylsulfanyl)ÂbicycloÂ[3.1.0]Âhexane-2,6-dicarboxylic
acid <b>14a</b> (LY2812223) was further characterized. Cocrystallization
of <b>14a</b> with the amino terminal domains of hmGlu<sub>2</sub> and hmGlu<sub>3</sub> combined with site-directed mutation studies
has clarified the underlying molecular basis of this unique pharmacology.
Evaluation of <b>14a</b> in a rat model responsive to mGlu<sub>2</sub> receptor activation coupled with a measure of central drug
disposition provides evidence that this molecule engages and activates
central mGlu<sub>2</sub> receptors in vivo
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
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-methylbicycloÂ[3.1.0]Âhexane-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