ABSTRACT
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. 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.
Subject(s)
Antidepressive Agents/pharmacology , Behavior, Animal/drug effects , Drug Discovery , Receptors, Metabotropic Glutamate/antagonists & inhibitors , Animals , Antidepressive Agents/chemical synthesis , Antidepressive Agents/chemistry , Brain/drug effects , Cyclohexanes/chemical synthesis , Cyclohexanes/chemistry , Cyclohexanes/pharmacology , Dose-Response Relationship, Drug , Humans , Male , Mice , Mice, Inbred Strains , Models, Molecular , Molecular Structure , Motor Activity/drug effects , Receptors, Metabotropic Glutamate/chemistry , Receptors, Metabotropic Glutamate/isolation & purification , Structure-Activity Relationship , SwimmingABSTRACT
Negative modulators of metabotropic glutamate 2 & 3 receptors demonstrate antidepressant-like activity in animal models and hold promise as novel therapeutic agents for the treatment of major depressive disorder. Herein we describe our efforts to prepare and optimize a series of conformationally constrained 3,4-disubstituted bicyclo[3.1.0]hexane glutamic acid analogs as orthosteric (glutamate site) mGlu2/3 receptor antagonists. This work led to the discovery of a highly potent and efficacious tool compound 18 (hmGlu2 IC50 46±14.2nM, hmGlu3 IC50=46.1±36.2nM). Compound 18 showed activity in the mouse forced swim test with a minimal effective dose (MED) of 1mg/kg ip. While in rat EEG studies it exhibited wake promoting effects at 3 and 10mg/kg ip without any significant effects on locomotor activity. Compound 18 thus represents a novel tool molecule for studying the impact of blocking mGlu2/3 receptors both in vitro and in vivo.
Subject(s)
Antidepressive Agents/chemistry , Antidepressive Agents/pharmacology , Depressive Disorder, Major/drug therapy , Glutamic Acid/analogs & derivatives , Glutamic Acid/pharmacology , Receptors, Metabotropic Glutamate/antagonists & inhibitors , Animals , Antidepressive Agents/pharmacokinetics , Bridged Bicyclo Compounds/chemistry , Bridged Bicyclo Compounds/pharmacokinetics , Bridged Bicyclo Compounds/pharmacology , Cell Line , Depressive Disorder, Major/metabolism , Dogs , Glutamic Acid/pharmacokinetics , Haplorhini , Hexanes/chemistry , Hexanes/pharmacokinetics , Hexanes/pharmacology , Humans , Madin Darby Canine Kidney Cells , Mice , Rats , Receptors, Metabotropic Glutamate/metabolismABSTRACT
The objective of the described research effort was to identify a novel serotonin and norepinephrine reuptake inhibitor (SNRI) with improved norepinephrine transporter activity and acceptable metabolic stability and exhibiting minimal drug-drug interaction. We describe herein the discovery of a series of 3-substituted pyrrolidines, exemplified by compound 1. Compound 1 is a selective SNRI in vitro and in vivo, has favorable ADME properties, and retains inhibitory activity in the formalin model of pain behavior. Compound 1 thus represents a potential new probe to explore utility of SNRIs in central nervous system disorders, including chronic pain conditions.
ABSTRACT
9-Borabicyclononane (9-BBN) has been utilized to protect functionalized amino acids for potential chemoselective side chain manipulation. The 9-BBN group imparts organic solubility to otherwise hydrophilic molecules and is tolerant of a wide range of reaction conditions. The high degree of solubility of these molecules in THF is particularly noteworthy. It is cleaved with either aqueous HCl or by exchange with ethylenediamine in methanol. [reaction: see text]
