Synthesis and Pharmacological Characterization of C4-(Thiotriazolyl)-substituted-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylates. Identification of (1R,2S,4R,5R,6R)-2-Amino-4-(1H-1,2,4-triazol-3-ylsulfanyl)bicyclo[3.1.0]hexane-2,6-dicarboxylic Acid (LY2812223), a Highly Potent, Functionally Selective mGlu₂ Receptor Agonist

Abstract

Identification of orthosteric mGlu(2/3) receptor agonists capable of discriminating between individual mGlu2 and mGlu3 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 (1S,2S,5R,6S)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylate 1 (LY354740) bearing C4-thiotriazole substituents. On the basis of second messenger responses in cells expressing other recombinant human mGlu2/3 subtypes, a number of high potency and efficacy mGlu2 receptor agonists exhibiting low potency mGlu3 partial agonist/antagonist activity were identified. From this, (1R,2S,4R,5R,6R)-2-amino-4-(1H-1,2,4-triazol-3-ylsulfanyl)bicyclo[3.1.0]hexane-2,6-dicarboxylic acid 14a (LY2812223) was further characterized. Cocrystallization of 14a with the amino terminal domains of hmGlu2 and hmGlu3 combined with site-directed mutation studies has clarified the underlying molecular basis of this unique pharmacology. Evaluation of 14a in a rat model responsive to mGlu2 receptor activation coupled with a measure of central drug disposition provides evidence that this molecule engages and activates central mGlu2 receptors in vivo.

Evaluation of single and multiple doses of a novel mGlu2 agonist, a potential antipsychotic therapy, in healthy subjects

“…Glutamate serves as the principal excitatory neurotransmitter in the mammalian central nervous system , and aberrant glutamate neurotransmission has been implicated in both psychiatric and neurologic disorders . Metabotropic glutamate (mGlu) receptors are plasma membrane‐associated G‐protein‐coupled proteins that function via presynaptic, postsynaptic, and glial mechanisms to modulate neuronal excitability . The mGlu2 and mGlu3 receptors are heavily distributed within cortical and limbic structures of the brain (e.g.…”

“…Consequently, mGlu2/3 receptor agonists have demonstrated efficacy in animal models of hyper‐glutamatergic tone (e.g. states associated with stress/anxiety or psychosis) . Clinical evaluation of two balanced mGlu2/3 receptor agonists has been reported, one in generalized anxiety disorder and one in schizophrenia, respectively .…”

“…LY2979165 (Figure A) is the alanine prodrug of 2812223 (Figure B), a selective and potent orthosteric mGlu2 receptor agonist . A GTP‐γ‐[ 35 S] functional binding assay was used to evaluate 2812223 mGlu2 pharmacology in human cortical brain tissue samples where it was found to be a partial mGlu2 agonist with an in vitro EC 50 value of 7.57 nM (unpublished data on file, Eli Lilly and Company , Indianapolis, IN, USA).…”

“…A GTP‐γ‐[ 35 S] functional binding assay was used to evaluate 2812223 mGlu2 pharmacology in human cortical brain tissue samples where it was found to be a partial mGlu2 agonist with an in vitro EC 50 value of 7.57 nM (unpublished data on file, Eli Lilly and Company , Indianapolis, IN, USA). It has shown activity in the phencyclidine‐evoked ambulation model in rats, an animal model of psychosis known to be sensitive to mGlu2‐receptor (and not to mGlu3‐receptor) activation . Two clinical studies were conducted to assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of LY2979165 and 2812223 following single and multiple doses of oral LY2979165 in healthy subjects to support future studies in patients with psychiatric conditions.…”

Computer-Aided Drug Design Approaches to Study Key Therapeutic Targets in Alzheimer’s Disease

“…More than 200 3D structures of apo-GPCRs, protein-, natural ligand-, agonist-, and antagonist-bound GPCRs have been solved so far (Table 1), in which the rhodopsin-like GPCRs (or class A GPCRs) have been the most reported class [42][43][44]. Additionally, the 3D structures of four subfamilies of secretin-like or class B GPCRs (Corticotropin-Releasing Factor Receptors, CRFRs; Calcitonin Receptor-Like Receptors, CRLRs; Glucagon-Like Peptide Receptors, GLPRs; ParaThyroid Hormone-related peptide Receptors, PTHRs) [347][348][349][350][351][352][353][354][355][356][357][358][359], two subfamilies of glutamate-like or class C GPCRs (metabotropic Glutamate Receptors, mGluRs; γ-AminoButyric Acid Receptors, GABARs) [360][361][362][363][364][365][366], one subfamily of frizzled/taste2-like or class F GPCR (Smoothened receptors, Smo) [367][368][369][370][371][372], and two subfamilies of adhesion GPCRs (Adhesion G-protein coupled Receptor G1, ADGRG1; Adhesion G-protein coupled Receptor L3, ADGRL3) [373][374][375] have been disclosed on PDB (reported until June 2017). algorithms are emerging [381,382].…”