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Title: 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

Journal Article · · Journal of Medicinal Chemistry
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  1. Eli Lilly and Company, Indianapolis, IN (United States)
  2. Centro de Investigación Lilly S.A. Avda. de la Industria, Madrid (Spain)
  3. Eli Lilly and Company, San Diego, CA (United States)
  4. Argonne National Lab. (ANL), Argonne, IL (United States)
  5. Eli Lilly and Company, Surrey (United Kingdom)
+ Show Author Affiliations

As part of our ongoing efforts to identify novel ligands for the metabotropic glutamate 2 and 3 (mGlu2/3) 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 mGlu2/3 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 mGlu2/3 antagonist. Further characterization of compound 19f binding to the human metabotropic 2 glutamate (hmGlu2) site was established by cocrystallization of this molecule with the amino terminal domain (ATD) of the hmGlu2 receptor protein. Here, 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 mGlu2 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 mGlu2 IC50 value.

Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States)
Sponsoring Organization:
USDOE Office of Science (SC)
Grant/Contract Number:
AC02-06CH11357
OSTI ID:
1340719
Journal Information:
Journal of Medicinal Chemistry, Vol. 59, Issue 24; ISSN 0022-2623
Publisher:
American Chemical Society (ACS)Copyright Statement
Country of Publication:
United States
Language:
ENGLISH
Citation Metrics:
Cited by: 29 works
Citation information provided by
Web of Science

References (61)

The Monoamine Hypothesis of Depression book January 2005
Glutamate Receptor Ion Channels: Structure, Regulation, and Function journal August 2010
Pharmacology and Functions of Metabotropic Glutamate Receptors journal April 1997
Pharmacological agents acting at subtypes of metabotropic glutamate receptors journal October 1999
Group II metabotropic glutamate receptor agonists as a potential drug for schizophrenia journal August 2010
Metabotropic glutamate receptors as novel targets for anxiety and stress disorders journal January 2005
Glutamate-based antidepressants: 20 years on journal November 2009
Targeting the glutamatergic system to develop novel, improved therapeutics for mood disorders journal May 2008
Metabotropic Glutamate Receptors in the Control of Mood Disorders journal April 2007
Neuroprotection by metabotropic glutamate receptor agonists: LY354740, LY379268 and LY389795 journal July 1999
Efficacy and Tolerability of an mGlu2/3 Agonist in the Treatment of Generalized Anxiety Disorder journal August 2007
Activation of mGlu2/3 receptors as a new approach to treat schizophrenia: a randomized Phase 2 clinical trial journal September 2007
AFQ056 in Parkinson patients with levodopa-induced dyskinesia: 13-week, randomized, dose-finding study: AFQ056 treatment of l -Dopa-Induced Dyskinesia journal July 2013
Distribution of metabotropic glutamate 2 and 3 receptors in the rat forebrain: Implication in emotional responses and central disinhibition journal March 2008
Distribution of metabotropic glutamate receptor mGluR3 in the mouse CNS: differential location relative to pre- and postsynaptic sites journal September 2001
Regulation of Neurotransmitter Release by Metabotropic Glutamate Receptors journal September 2000
Lack of effect of LY314582 (a group 2 metabotropic glutamate receptor agonist) on phencyclidine-induced locomotor activity in metabotropic glutamate receptor 2 knockout mice journal May 2000
Evidence for the Role of Metabotropic Glutamate (mGlu)2 Not mGlu3 Receptors in the Preclinical Antipsychotic Pharmacology of the mGlu2/3 Receptor Agonist (–)-(1 R, 4 S ,5 S ,6 S )-4-Amino-2-sulfonylbicyclo[3.1.0]hexane-4,6-dicarboxylic Acid (LY404039) journal April 2008
mGlu2 Metabotropic Glutamate Receptors Restrain Inflammatory Pain and Mediate the Analgesic Activity of Dual mGlu2/mGlu3 Receptor Agonists journal January 2011
Metabotropic Glutamate Receptors Differentially Regulate GABAergic Inhibition in Thalamus journal December 2006
Metabotropic glutamate receptor 3 activation is required for long-term depression in medial prefrontal cortex and fear extinction journal January 2015
The Use of Knock-Out Mice Unravels Distinct Roles for mGlu2 and mGlu3 Metabotropic Glutamate Receptors in Mechanisms of Neurodegeneration/Neuroprotection journal August 2007
Impairment of Hippocampal Mossy Fiber LTD in Mice Lacking mGluR2 journal August 1996
Presynaptic Group II mGluR Inhibition of Short-Term Depression in the Medial Perforant Path of the Dentate Gyrus In Vitro journal June 2001
Cocaine and Kindling Alter the Sensitivity of Group II and III Metabotropic Glutamate Receptors in the Central Amygdala journal August 2000
Differential regulation of synaptic transmission by mGlu2 and mGlu3 at the perforant path inputs to the dentate gyrus and CA1 revealed in mGlu2 -/- mice journal August 2002
mGluR2/3 blockade produces rapid and long-lasting reversal of anhedonia caused by chronic stress exposure journal January 2013
mTOR activation is required for the antidepressant effects of mGluR2/3 blockade journal November 2011
Role of BDNF/TrkB signaling in antidepressant-like effects of a group II metabotropic glutamate receptor antagonist in animal models of depression journal February 2013
The Antidepressant Effects of an mGlu2/3 Receptor Antagonist and Ketamine Require AMPA Receptor Stimulation in the mPFC and Subsequent Activation of the 5-HT Neurons in the DRN journal August 2015
Antidepressant effects of ketamine in depressed patients journal February 2000
A Randomized Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Major Depression journal August 2006
Riluzole for relapse prevention following intravenous ketamine in treatment-resistant depression: a pilot randomized, placebo-controlled continuation trial journal February 2010
Ketamine for Depression: Where Do We Go from Here? journal October 2012
Ketamine for Treatment-Resistant Unipolar Depression: Current Evidence journal January 2012
Antidepressant Efficacy of Ketamine in Treatment-Resistant Major Depression: A Two-Site Randomized Controlled Trial journal October 2013
2-Substituted (2 SR )-2-Amino-2-((1 SR ,2 SR )-2-carboxycycloprop-1-yl)glycines as Potent and Selective Antagonists of Group II Metabotropic Glutamate Receptors. 2. Effects of Aromatic Substitution, Pharmacological Characterization, and Bioavailability journal January 1998
LY341495 is a nanomolar potent and selective antagonist of group II metabotropic glutamate receptors journal January 1998
MGS0039: a potent and selective group II metabotropic glutamate receptor antagonist with antidepressant-like activity journal March 2004
An mGluR2/3 antagonist, MGS0039, exerts antidepressant and anxiolytic effects in behavioral models in rats journal April 2006
On the mechanism of the antidepressant-like action of group II mGlu receptor antagonist, MGS0039 journal August 2010
Recent Progress in the Synthesis and Characterization of Group II Metabotropic Glutamate Receptor Allosteric Modulators journal April 2011
Ketamine as a new treatment for depression: A review of its efficacy and adverse effects journal May 2013
Design, Synthesis, and Pharmacological Characterization of (+)-2-Aminobicyclo[3.1.0]hexane-2,6-dicarboxylic Acid (LY354740):  A Potent, Selective, and Orally Active Group 2 Metabotropic Glutamate Receptor Agonist Possessing Anticonvulsant and Anxiolytic Properties journal February 1997
LY354740 is a Potent and Highly Selective Group II Metabotropic Glutamate Receptor Agonist in Cells Expressing Human Glutamate Receptors journal January 1997
Synthesis and Metabotropic Glutamate Receptor Activity of S-Oxidized Variants of (−)-4-Amino-2-thiabicyclo-[3.1.0]hexane-4,6-dicarboxylate:  Identification of Potent, Selective, and Orally Bioavailable Agonists for mGlu2/3 Receptors journal January 2007
Pharmacological and Pharmacokinetic Properties of a Structurally Novel, Potent, and Selective Metabotropic Glutamate 2/3 Receptor Agonist: In Vitro Characterization of Agonist (–)-(1 R ,4 S ,5 S ,6 S )-4-Amino-2-sulfonylbicyclo[3.1.0]-hexane-4,6-dicarboxylic Acid (LY404039) journal January 2007
In vivo pharmacological characterization of the structurally novel, potent, selective mGlu2/3 receptor agonist LY404039 in animal models of psychiatric disorders journal March 2007
Synthesis and Pharmacological Characterization of 4-Substituted-2-Aminobicyclo[3.1.0]hexane-2,6-dicarboxylates: Identification of New Potent and Selective Metabotropic Glutamate 2/3 Receptor Agonists journal June 2013
Design, Development, and Scale-Up of a Selective meso -Epoxide Desymmetrization Process journal May 2007
Säureamid-Reaktionen, L; Orthoamide, I Darstellung und Eigenschaften der Amidacetale und Aminalester journal January 1968
Highly enantioselective borane reduction of ketones catalyzed by chiral oxazaborolidines. Mechanism and synthetic implications journal September 1987
CNS distribution of metabotropic glutamate 2 and 3 receptors: Transgenic mice and [3H]LY459477 autoradiography journal March 2013
Synthesis and Pharmacological Characterization of C4-Disubstituted Analogs of 1 S ,2 S ,5 R ,6 S -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 journal February 2015
Synthesis and Pharmacological Characterization of C 4-(Thiotriazolyl)-substituted-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylates. Identification of (1 R ,2 S ,4 R ,5 R ,6 R )-2-Amino-4-(1 H -1,2,4-triazol-3-ylsulfanyl)bicyclo[3.1.0]hexane-2,6-dicarboxylic Acid (LY2812223), a Highly Potent, Functionally Selective mGlu 2 Receptor Agonist journal September 2015
A family of metabotropic glutamate receptors journal January 1992
Group III Metabotropic Glutamate Receptors: Pharmacology, Physiology and Therapeutic Potential journal August 2014
Structures of the extracellular regions of the group II/III metabotropic glutamate receptors journal February 2007
Crystal Structure of Metabotropic glutamate receptor 3 precursor in presence of LY341495 antagonist text January 2011
In vitro pharmacological and rat pharmacokinetic characterization of LY3020371, a potent and selective mGlu 2/3 receptor antagonist journal March 2017
mGlu2/3 Agonist-Induced Hyperthermia: An In Vivo Assay for Detection of mGlu2/3 Receptor Antagonism and its Relation to Antidepressant-Like Efficacy in Mice journal July 2013

Cited By (4)

Structural insights into the activation of metabotropic glutamate receptors journal January 2019
Decoding the Mechanism of Action of Rapid-Acting Antidepressant Treatment Strategies: Does Gender Matter? journal February 2019
Current and Future Challenges in GPCR Drug Discovery book November 2017
Recent advances in the medicinal chemistry of group II and group III mGlu receptors journal January 2017

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Related Subjects

60 APPLIED LIFE SCIENCES
antagonists
substituents
selectivity
screening assays
receptors
mGlu2/3 antagonists
LY3020371.HCl
LY341495