Synthesis and Pharmacological Characterization of C4_β-Amide-Substituted 2-Aminobicyclo[3.1.0]hexane-2,6-dicarboxylates. Identification of (1S,2S,4S,5R,6S)-2-Amino-4-[(3-methoxybenzoyl)amino]bicyclo[3.1.0]hexane-2,6-dicarboxylic Acid (LY2794193), a Highly Potent and Selective mGlu₃Receptor Agonist

Abstract

Multiple therapeutic opportunities have been suggested for compounds capable of selective activation of metabotropic glutamate 3 (mGlu) receptors, but small molecule tools are lacking. As part of our ongoing efforts to identify potent, selective, and systemically bioavailable agonists for mGlu and mGlu receptor subtypes, a series of C4-N-linked variants of (1 S,2 S,5 R,6 S)-2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid 1 (LY354740) were prepared and evaluated for both mGlu and mGlu receptor binding affinity and functional cellular responses. From this investigation we identified (1 S,2 S,4 S,5 R,6 S)-2-amino-4-[(3-methoxybenzoyl)amino]bicyclo[3.1.0]hexane-2,6-dicarboxylic acid 8p (LY2794193), a molecule that demonstrates remarkable mGlu receptor selectivity. Crystallization of 8p with the amino terminal domain of hmGlu revealed critical binding interactions for this ligand with residues adjacent to the glutamate binding site, while pharmacokinetic assessment of 8p combined with its effect in an mGlu receptor-dependent behavioral model provides estimates for doses of this compound that would be expected to selectively engage and activate central mGlu receptors in vivo.

Cryo-EM structures of brain-derived G protein-coupled receptors

“…This site appears to form interactions with both the upper and lower VFT lobes, which would ultimately assist in domain closure. This is consistent with the relatively stronger intrinsic agonist activity and efficacy-drive allostery observed for chloride at mGluR3, with the exception of LY27, which our data supporting prior structural studies 61 showing it perturbs this site (Figures 6D-6E). Direct visualization of these ion-binding sites within the endogenous receptors, and our structural finding that mGluR3 is only detected in the active states, supports a unique physiological role for chloride group II mGluR function in the brain.…”

“…Based on these clear map features, and strong precedent from the prior mutagenesis studies 57,58 , we have tentatively modelled chloride at this site in mGluR3 (“site 2”; Figure 6C). It is important to note these assignments are also strongly supported by prior crystallographic studies that show clear halide spherical OMIT F o -F c signals at site 1 (in mGluR2 and mGluR3) and site 2 (mGluR3 only; Figure S10) 59–61 .…”

Discovery of Novel Central Nervous System Penetrant Metabotropic Glutamate Receptor Subtype 2 (mGlu 2 ) Negative Allosteric Modulators (NAMs) Based on Functionalized Pyrazolo[1,5- a ]pyrimidine-5-carboxamide and Thieno[3,2- b ]pyridine-5-carboxamide Cores

“…Our scaffold hopping strategy is depicted in Figure and centered on cyclization at the benzylic site to incorporate a fused 5-membered heterocycle (with or without a heteroatom at the ring fusion site) to produce two distinct 5,6-heterobicyclic systems, a pyrazolo­[1,5- a ]­pyrimidine-5-carboxamide core 5 or a thieno­[3,2- b ]­pyridine-5-carboxamide core 6 . We desired a route that would allow significant diversity to sample replacements for the western N -Me pyrazole moiety and efficient entry to the more limited set of substituted aromatic moieties (Ar) that engender mGlu 2 NAM potency/efficacy. − …”

Plasticity of ventral tegmental area disturbance during abstinence after repeated amphetamine exposure: restoration by selective activation of group II metabotropic glutamate receptors

“…More recently, activation of mGluR3 has been reported to rescue schizophrenia-like behaviour ( Dogra et al, 2024 ) and to counteract cognitive deficits that were caused by NMDA receptor antagonism through actions on hippocampal pyramidal neurons ( Dogra et al, 2021 ). Moreover, in the rat PCP model of schizophrenia, activation of mGluR3 by the selective agonist LY2794193 was shown to prevent drug-induced hyperlocomotion ( Monn et al, 2018 ). Here, acute administration of LY2794193 during prolonged abstinence from AMPH tuned hyperdopaminergic VTA activity as correlate of psychotic symptoms down to physiological levels when applied directly into vHPC or systemically.…”

“…The dose of AMPH was selected for consistency with previous studies in rodents ( Lodge and Grace, 2008 ; Belujon et al, 2016 ) and humans ( Berman et al, 2009 ). To assess the capability of group II mGluRs of counteracting abstinence, we employed the following compounds: a general group II mGluR agonist LY354740 (3 mg/kg) ( Schoepp et al, 2003 ), the selective mGluR2 PAM LY487379 (30 mg/kg) ( Nikiforuk et al, 2010 ; Mango et al, 2019 ), and selective mGluR3 agonist LY2794193 (10 mg/kg) ( Monn et al, 2018 ).…”