title: 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.
authors: Discovery Chemistry Research and Technologies, ‡Quantitative Biology, §Structural Biology, ∥Drug Disposition and ⊥Neuroscience Research, Eli Lilly and Company , Lilly Corporate Center, Drop 0510, Indianapolis, Indiana 46285, United States.
authors: James A
authors: JA
authors: Monn
authors: Discovery Chemistry Research and Technologies, ‡Quantitative Biology, §Structural Biology, ∥Drug Disposition and ⊥Neuroscience Research, Eli Lilly and Company , Lilly Corporate Center, Drop 0510, Indianapolis, Indiana 46285, United States.
authors: Lourdes
authors: L
authors: Prieto
authors: Discovery Chemistry Research and Technologies, ‡Quantitative Biology, §Structural Biology, ∥Drug Disposition and ⊥Neuroscience Research, Eli Lilly and Company , Lilly Corporate Center, Drop 0510, Indianapolis, Indiana 46285, United States.
authors: Lorena
authors: L
authors: Taboada
authors: Discovery Chemistry Research and Technologies, ‡Quantitative Biology, §Structural Biology, ∥Drug Disposition and ⊥Neuroscience Research, Eli Lilly and Company , Lilly Corporate Center, Drop 0510, Indianapolis, Indiana 46285, United States.
authors: Junliang
authors: J
authors: Hao
authors: Discovery Chemistry Research and Technologies, ‡Quantitative Biology, §Structural Biology, ∥Drug Disposition and ⊥Neuroscience Research, Eli Lilly and Company , Lilly Corporate Center, Drop 0510, Indianapolis, Indiana 46285, United States.
authors: Matthew R
authors: MR
authors: Reinhard
authors: Discovery Chemistry Research and Technologies, ‡Quantitative Biology, §Structural Biology, ∥Drug Disposition and ⊥Neuroscience Research, Eli Lilly and Company , Lilly Corporate Center, Drop 0510, Indianapolis, Indiana 46285, United States.
authors: Steven S
authors: SS
authors: Henry
authors: Discovery Chemistry Research and Technologies, ‡Quantitative Biology, §Structural Biology, ∥Drug Disposition and ⊥Neuroscience Research, Eli Lilly and Company , Lilly Corporate Center, Drop 0510, Indianapolis, Indiana 46285, United States.
authors: Christopher D
authors: CD
authors: Beadle
authors: Discovery Chemistry Research and Technologies, ‡Quantitative Biology, §Structural Biology, ∥Drug Disposition and ⊥Neuroscience Research, Eli Lilly and Company , Lilly Corporate Center, Drop 0510, Indianapolis, Indiana 46285, United States.
authors: Lesley
authors: L
authors: Walton
authors: Discovery Chemistry Research and Technologies, ‡Quantitative Biology, §Structural Biology, ∥Drug Disposition and ⊥Neuroscience Research, Eli Lilly and Company , Lilly Corporate Center, Drop 0510, Indianapolis, Indiana 46285, United States.
authors: Teresa
authors: T
authors: Man
authors: Discovery Chemistry Research and Technologies, ‡Quantitative Biology, §Structural Biology, ∥Drug Disposition and ⊥Neuroscience Research, Eli Lilly and Company , Lilly Corporate Center, Drop 0510, Indianapolis, Indiana 46285, United States.
authors: Helene
authors: H
authors: Rudyk
authors: Discovery Chemistry Research and Technologies, ‡Quantitative Biology, §Structural Biology, ∥Drug Disposition and ⊥Neuroscience Research, Eli Lilly and Company , Lilly Corporate Center, Drop 0510, Indianapolis, Indiana 46285, United States.
authors: Barry
authors: B
authors: Clark
authors: Discovery Chemistry Research and Technologies, ‡Quantitative Biology, §Structural Biology, ∥Drug Disposition and ⊥Neuroscience Research, Eli Lilly and Company , Lilly Corporate Center, Drop 0510, Indianapolis, Indiana 46285, United States.
authors: David
authors: D
authors: Tupper
authors: Discovery Chemistry Research and Technologies, ‡Quantitative Biology, §Structural Biology, ∥Drug Disposition and ⊥Neuroscience Research, Eli Lilly and Company , Lilly Corporate Center, Drop 0510, Indianapolis, Indiana 46285, United States.
authors: S Richard
authors: SR
authors: Baker
authors: Discovery Chemistry Research and Technologies, ‡Quantitative Biology, §Structural Biology, ∥Drug Disposition and ⊥Neuroscience Research, Eli Lilly and Company , Lilly Corporate Center, Drop 0510, Indianapolis, Indiana 46285, United States.
authors: Carlos
authors: C
authors: Lamas
authors: Discovery Chemistry Research and Technologies, ‡Quantitative Biology, §Structural Biology, ∥Drug Disposition and ⊥Neuroscience Research, Eli Lilly and Company , Lilly Corporate Center, Drop 0510, Indianapolis, Indiana 46285, United States.
authors: Carlos
authors: C
authors: Montero
authors: Discovery Chemistry Research and Technologies, ‡Quantitative Biology, §Structural Biology, ∥Drug Disposition and ⊥Neuroscience Research, Eli Lilly and Company , Lilly Corporate Center, Drop 0510, Indianapolis, Indiana 46285, United States.
authors: Alicia
authors: A
authors: Marcos
authors: Discovery Chemistry Research and Technologies, ‡Quantitative Biology, §Structural Biology, ∥Drug Disposition and ⊥Neuroscience Research, Eli Lilly and Company , Lilly Corporate Center, Drop 0510, Indianapolis, Indiana 46285, United States.
authors: Jaime
authors: J
authors: Blanco
authors: Discovery Chemistry Research and Technologies, ‡Quantitative Biology, §Structural Biology, ∥Drug Disposition and ⊥Neuroscience Research, Eli Lilly and Company , Lilly Corporate Center, Drop 0510, Indianapolis, Indiana 46285, United States.
authors: Mark
authors: M
authors: Bures
authors: Discovery Chemistry Research and Technologies, ‡Quantitative Biology, §Structural Biology, ∥Drug Disposition and ⊥Neuroscience Research, Eli Lilly and Company , Lilly Corporate Center, Drop 0510, Indianapolis, Indiana 46285, United States.
authors: David K
authors: DK
authors: Clawson
authors: Discovery Chemistry Research and Technologies, ‡Quantitative Biology, §Structural Biology, ∥Drug Disposition and ⊥Neuroscience Research, Eli Lilly and Company , Lilly Corporate Center, Drop 0510, Indianapolis, Indiana 46285, United States.
authors: Shane
authors: S
authors: Atwell
authors: Discovery Chemistry Research and Technologies, ‡Quantitative Biology, §Structural Biology, ∥Drug Disposition and ⊥Neuroscience Research, Eli Lilly and Company , Lilly Corporate Center, Drop 0510, Indianapolis, Indiana 46285, United States.
authors: Frances
authors: F
authors: Lu
authors: Discovery Chemistry Research and Technologies, ‡Quantitative Biology, §Structural Biology, ∥Drug Disposition and ⊥Neuroscience Research, Eli Lilly and Company , Lilly Corporate Center, Drop 0510, Indianapolis, Indiana 46285, United States.
authors: Jing
authors: J
authors: Wang
authors: Discovery Chemistry Research and Technologies, ‡Quantitative Biology, §Structural Biology, ∥Drug Disposition and ⊥Neuroscience Research, Eli Lilly and Company , Lilly Corporate Center, Drop 0510, Indianapolis, Indiana 46285, United States.
authors: Marijane
authors: M
authors: Russell
authors: Discovery Chemistry Research and Technologies, ‡Quantitative Biology, §Structural Biology, ∥Drug Disposition and ⊥Neuroscience Research, Eli Lilly and Company , Lilly Corporate Center, Drop 0510, Indianapolis, Indiana 46285, United States.
authors: Beverly A
authors: BA
authors: Heinz
authors: Discovery Chemistry Research and Technologies, ‡Quantitative Biology, §Structural Biology, ∥Drug Disposition and ⊥Neuroscience Research, Eli Lilly and Company , Lilly Corporate Center, Drop 0510, Indianapolis, Indiana 46285, United States.
authors: Xushan
authors: X
authors: Wang
authors: Discovery Chemistry Research and Technologies, ‡Quantitative Biology, §Structural Biology, ∥Drug Disposition and ⊥Neuroscience Research, Eli Lilly and Company , Lilly Corporate Center, Drop 0510, Indianapolis, Indiana 46285, United States.
authors: Joan H
authors: JH
authors: Carter
authors: Discovery Chemistry Research and Technologies, ‡Quantitative Biology, §Structural Biology, ∥Drug Disposition and ⊥Neuroscience Research, Eli Lilly and Company , Lilly Corporate Center, Drop 0510, Indianapolis, Indiana 46285, United States.
authors: Brian G
authors: BG
authors: Getman
authors: Discovery Chemistry Research and Technologies, ‡Quantitative Biology, §Structural Biology, ∥Drug Disposition and ⊥Neuroscience Research, Eli Lilly and Company , Lilly Corporate Center, Drop 0510, Indianapolis, Indiana 46285, United States.
authors: John T
authors: JT
authors: Catlow
authors: Discovery Chemistry Research and Technologies, ‡Quantitative Biology, §Structural Biology, ∥Drug Disposition and ⊥Neuroscience Research, Eli Lilly and Company , Lilly Corporate Center, Drop 0510, Indianapolis, Indiana 46285, United States.
authors: Steven
authors: S
authors: Swanson
authors: Discovery Chemistry Research and Technologies, ‡Quantitative Biology, §Structural Biology, ∥Drug Disposition and ⊥Neuroscience Research, Eli Lilly and Company , Lilly Corporate Center, Drop 0510, Indianapolis, Indiana 46285, United States.
authors: Bryan G
authors: BG
authors: Johnson
authors: Discovery Chemistry Research and Technologies, ‡Quantitative Biology, §Structural Biology, ∥Drug Disposition and ⊥Neuroscience Research, Eli Lilly and Company , Lilly Corporate Center, Drop 0510, Indianapolis, Indiana 46285, United States.
authors: David B
authors: DB
authors: Shaw
authors: Discovery Chemistry Research and Technologies, ‡Quantitative Biology, §Structural Biology, ∥Drug Disposition and ⊥Neuroscience Research, Eli Lilly and Company , Lilly Corporate Center, Drop 0510, Indianapolis, Indiana 46285, United States.
authors: David L
authors: DL
authors: McKinzie
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D001667:Binding, Competitive; D001643:Bridged Bicyclo Compounds / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D004285:Dogs; D054333:Drug Partial Agonism; D006801:Humans; D008297:Male; D051379:Mice; D008958:Models, Molecular; D009043:Motor Activity / Q000187:drug effects; D016297:Mutagenesis, Site-Directed; D017434:Protein Structure, Tertiary; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D013237:Stereoisomerism; D014230:Triazoles / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D001643:Bridged Bicyclo Compounds; C000603803:LY2812223; D018094:Receptors, Metabotropic Glutamate; D014230:Triazoles; C108822:metabotropic glutamate receptor 2; C102718:metabotropic glutamate receptor 3; D000242:Cyclic AMP; D002118:Calcium