Discovery of (1S,2R,3S,4S,5R,6R)-2-Amino-3-[(3,4-difluorophenyl)sulfanylmethyl]-4-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic Acid Hydrochloride (LY3020371·HCl): A Potent, Metabotropic Glutamate 2/3 Receptor Antagonist with Antidepressant-Like Activity

Abstract

As part of our ongoing efforts to identify novel ligands for the metabotropic glutamate 2 and 3 (mGlu) receptors, we have incorporated substitution at the C3 and C4 positions of the (1S,2R,5R,6R)-2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid scaffold to generate mGlu antagonists. Exploration of this structure-activity relationship (SAR) led to the identification of (1S,2R,3S,4S,5R,6R)-2-amino-3-[(3,4-difluorophenyl)sulfanylmethyl]-4-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid hydrochloride (LY3020371·HCl, 19f), a potent, selective, and maximally efficacious mGlu antagonist. Further characterization of compound 19f binding to the human metabotropic 2 glutamate (hmGlu) site was established by cocrystallization of this molecule with the amino terminal domain (ATD) of the hmGlu receptor protein. The resulting cocrystal structure revealed the specific ligand-protein interactions, which likely explain the high affinity of 19f for this site and support its functional mGlu antagonist pharmacology. Further characterization of 19f in vivo demonstrated an antidepressant-like signature in the mouse forced-swim test (mFST) assay when brain levels of this compound exceeded the cellular mGlu IC value.

International Union of Basic and Clinical Pharmacology. CVIII. Calcium-Sensing Receptor Nomenclature, Pharmacology, and Function

“…2D) (Geng et al, 2016). This change is consistent with other X-ray structures of class C ECDs (Muto et al, 2007;Chappell et al, 2016), likely driving a similar reorientation of the 7TM domains as seen in the mGlu 5 cryo-EM structure a "transitionstate" that is partially active but not coupled to G proteins (Koehl et al, 2019). This reorientation is sustained by the rigid CR domain and its nine Cys residues, which form five covalent disulfide bonds: four within the CR domain and one that anchors the CR domain to lobe 2 of the VFT.…”

Structural insights into the activation of metabotropic glutamate receptors

“…The majority of interactions between Nb43 and mGlu5 are polar (Figure 2b) and involve poorly conserved residues amongst mGlu receptor subtypes (Extended Data Figure 1c), suggesting Nb43 would be a subtype-selective PAM of mGlu5. Overall, the architecture of this VFT dimer is that of an elusive “Aoo” (active open-open) form 19 that has been observed very infrequently in crystal structures of antagonist-bound ECDs of mGlu1 (PDB 3SK9) and mGlu2 (PDB 5KZN) 20 . The Aoo form is characterized by the close proximity of the VFT bottom lobes despite the flytraps being open (Figure 2d, middle panel).…”

Decoding the Mechanism of Action of Rapid-Acting Antidepressant Treatment Strategies: Does Gender Matter?

“…In addition, the direct and specific manipulation of type 2 and 3 metabotropic glutamate receptors emerged as an interesting approach. By enhancing AMPA receptor signalling, antagonists of these receptors produced antidepressant-like effects in rodents, without ketamine-related side effects [85,86,87]. GABA A receptor signalling reduces glutamate transmission, which explains why GABA receptor antagonists and modulators are also important in the search for rapid-acting antidepressant drugs.…”