title: Synthesis and pharmacological characterization of C4-disubstituted analogs of 1S,2S,5R,6S-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.
abstract: As part of our ongoing research to identify novel agents acting at metabotropic glutamate 2 (mGlu2) and 3 (mGlu3) receptors, we have previously reported the identification of the C4α-methyl analog of mGlu2/3 receptor agonist 1 (LY354740). This molecule, 1S,2S,4R,5R,6S-2-amino-4-methylbicyclo[3.1.0]hexane-2,6-dicarboxylate 2 (LY541850), exhibited an unexpected mGlu2 agonist/mGlu3 antagonist pharmacological profile, whereas the C4β-methyl diastereomer (3) possessed dual mGlu2/3 receptor agonist activity. We have now further explored this structure-activity relationship through the preparation of cyclic and acyclic C4-disubstituted analogs of 1, leading to the identification of C4-spirocyclopropane 5 (LY2934747), a novel, potent, and systemically bioavailable mGlu2/3 receptor agonist which exhibits both antipsychotic and analgesic properties in vivo. In addition, through the combined use of protein-ligand X-ray crystallography employing recombinant human mGlu2/3 receptor amino terminal domains, molecular modeling, and site-directed mutagenesis, a molecular basis for the observed pharmacological profile of compound 2 is proposed.
authors.affiliation: Discovery Chemistry Research and Technologies, ‡Quantitative Biology, §Structural Biology, ∥Drug Disposition, and ⊥Neuroscience Research, Eli Lilly and Company , Indianapolis, Indiana 46285, United States.
authors.forename: James A
authors.initials: JA
authors.lastname: Monn
authors.forename: Lourdes
authors.initials: L
authors.lastname: Prieto
authors.forename: Lorena
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authors.lastname: Taboada
authors.forename: Concepcion
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authors.lastname: Pedregal
authors.forename: Junliang
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authors.lastname: Hao
authors.forename: Matt R
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authors.lastname: Reinhard
authors.forename: Steven S
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authors.lastname: Goldsmith
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Beadle
authors.forename: Lesley
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authors.lastname: Walton
authors.forename: Teresa
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authors.lastname: Man
authors.forename: Helene
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authors.lastname: Rudyk
authors.forename: Barry
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authors.lastname: Clark
authors.forename: David
authors.initials: D
authors.lastname: Tupper
authors.forename: S Richard
authors.initials: SR
authors.lastname: Baker
authors.forename: Carlos
authors.initials: C
authors.lastname: Lamas
authors.forename: Carlos
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authors.lastname: Montero
authors.forename: Alicia
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authors.lastname: Marcos
authors.forename: Jaime
authors.initials: J
authors.lastname: Blanco
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authors.initials: M
authors.lastname: Bures
authors.forename: David K
authors.initials: DK
authors.lastname: Clawson
authors.forename: Shane
authors.initials: S
authors.lastname: Atwell
authors.forename: Frances
authors.initials: F
authors.lastname: Lu
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.forename: Marijane
authors.initials: M
authors.lastname: Russell
authors.forename: Beverly A
authors.initials: BA
authors.lastname: Heinz
authors.forename: Xushan
authors.initials: X
authors.lastname: Wang
authors.forename: Joan H
authors.initials: JH
authors.lastname: Carter
authors.forename: Chuanxi
authors.initials: C
authors.lastname: Xiang
authors.forename: John T
authors.initials: JT
authors.lastname: Catlow
authors.forename: Steven
authors.initials: S
authors.lastname: Swanson
authors.forename: Helen
authors.initials: H
authors.lastname: Sanger
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Broad
authors.forename: Michael P
authors.initials: MP
authors.lastname: Johnson
authors.forename: Kelly L
authors.initials: KL
authors.lastname: Knopp
authors.forename: Rosa M A
authors.initials: RM
authors.lastname: Simmons
authors.forename: Bryan G
authors.initials: BG
authors.lastname: Johnson
authors.forename: David B
authors.initials: DB
authors.lastname: Shaw
authors.forename: David L
authors.initials: DL
authors.lastname: McKinzie
mesh_terms: D000818:Animals; D001643:Bridged Bicyclo Compounds / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D006801:Humans; D008297:Male; D008958:Models, Molecular; D017434:Protein Structure, Tertiary; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists* / Q000737:chemistry / Q000235:genetics; D013141:Spiro Compounds / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*
chemical_list: C000597469:2-aminospiro(bicyclo(3.1.0)hexane-4,1'-cyclopropane)-2,6-dicarboxylic acid; D001643:Bridged Bicyclo Compounds; D018094:Receptors, Metabotropic Glutamate; D013141:Spiro Compounds; C108822:metabotropic glutamate receptor 2; C102718:metabotropic glutamate receptor 3