title: Translational Pharmacology of the Metabotropic Glutamate 2 Receptor-Preferring Agonist LY2812223 in the Animal and Human Brain.
abstract: LY2812223 [(1R,2S,4R,5R,6R)-2-amino-4-(1H-1,2,4-triazol-3-ylsulfanyl)bicyclo[3.1.0]hexane-2,6-dicarboxylic acid] was identified via structure-activity studies arising from the potent metabotropic glutamate mGlu2/3 receptor agonist LY354740 [(+)-2-aminobicyclo[3.1.0] hexane-2,6-dicarboxylic acid] as an mGlu2-preferring agonist. This pharmacology was determined using stably transfected cells containing either the human mGlu2 or mGlu3 receptor. We extended the pharmacological evaluation of LY2812223 to native brain tissues derived from relevant species used for preclinical drug development as well as human postmortem brain tissue. This analysis was conducted to ensure pharmacological translation from animals to human subjects in subsequent clinical studies. A guanosine 5'-O-(3-[35S]thio)triphosphate (GTPγS) functional binding assay, a method for measuring Gi-coupled signaling that is inherent to the group 2 mGlu receptors, was used to evaluate LY2812223 pharmacology of native mGlu receptors in mouse, rat, nonhuman primate, and human cortical brain tissue samples. In native tissue membranes, LY2812223 unexpectedly acted as a partial agonist across all species tested. Activity of LY2812223 was lost in cortical membranes collected from mGlu2 knockout mice, but not those from mGlu3 knockout mice, providing additional support for mGlu2-preferring activity. Other signal transduction assays were used for comparison with the GTP binding assay (cAMP, calcium mobilization, and dynamic mass redistribution). In ectopic cell line-based assays, LY2812223 displayed near maximal agonist responses at the mGlu2 receptor across all assay formats, while it showed no functional agonist activity at the mGlu3 receptor except in the cAMP assay. In native brain slices or membranes that express both mGlu2 and mGlu3 receptors, LY2812223 displayed unexpected partial agonist activity, which may suggest a functional interplay between these receptor subtypes in the brain.
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana (C.C.F., D.A.S., Y.T., A.Q., H.X., M.W., E.S., E.N., C.X., B.H., D.L.M., J.A.M.); and Lilly Research Laboratories, Eli Lilly and Company, Alcobendas, Spain (L.P.) felder_christian@lilly.com.
authors.forename: Christian C
authors.initials: CC
authors.lastname: Felder
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana (C.C.F., D.A.S., Y.T., A.Q., H.X., M.W., E.S., E.N., C.X., B.H., D.L.M., J.A.M.); and Lilly Research Laboratories, Eli Lilly and Company, Alcobendas, Spain (L.P.).
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Schober
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana (C.C.F., D.A.S., Y.T., A.Q., H.X., M.W., E.S., E.N., C.X., B.H., D.L.M., J.A.M.); and Lilly Research Laboratories, Eli Lilly and Company, Alcobendas, Spain (L.P.).
authors.forename: Yuan
authors.initials: Y
authors.lastname: Tu
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana (C.C.F., D.A.S., Y.T., A.Q., H.X., M.W., E.S., E.N., C.X., B.H., D.L.M., J.A.M.); and Lilly Research Laboratories, Eli Lilly and Company, Alcobendas, Spain (L.P.).
authors.forename: Anne
authors.initials: A
authors.lastname: Quets
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana (C.C.F., D.A.S., Y.T., A.Q., H.X., M.W., E.S., E.N., C.X., B.H., D.L.M., J.A.M.); and Lilly Research Laboratories, Eli Lilly and Company, Alcobendas, Spain (L.P.).
authors.forename: Hongling
authors.initials: H
authors.lastname: Xiao
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana (C.C.F., D.A.S., Y.T., A.Q., H.X., M.W., E.S., E.N., C.X., B.H., D.L.M., J.A.M.); and Lilly Research Laboratories, Eli Lilly and Company, Alcobendas, Spain (L.P.).
authors.forename: Marla
authors.initials: M
authors.lastname: Watt
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana (C.C.F., D.A.S., Y.T., A.Q., H.X., M.W., E.S., E.N., C.X., B.H., D.L.M., J.A.M.); and Lilly Research Laboratories, Eli Lilly and Company, Alcobendas, Spain (L.P.).
authors.forename: Ed
authors.initials: E
authors.lastname: Siuda
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana (C.C.F., D.A.S., Y.T., A.Q., H.X., M.W., E.S., E.N., C.X., B.H., D.L.M., J.A.M.); and Lilly Research Laboratories, Eli Lilly and Company, Alcobendas, Spain (L.P.).
authors.forename: Eric
authors.initials: E
authors.lastname: Nisenbaum
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana (C.C.F., D.A.S., Y.T., A.Q., H.X., M.W., E.S., E.N., C.X., B.H., D.L.M., J.A.M.); and Lilly Research Laboratories, Eli Lilly and Company, Alcobendas, Spain (L.P.).
authors.forename: Chuanxi
authors.initials: C
authors.lastname: Xiang
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana (C.C.F., D.A.S., Y.T., A.Q., H.X., M.W., E.S., E.N., C.X., B.H., D.L.M., J.A.M.); and Lilly Research Laboratories, Eli Lilly and Company, Alcobendas, Spain (L.P.).
authors.forename: Beverly
authors.initials: B
authors.lastname: Heinz
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana (C.C.F., D.A.S., Y.T., A.Q., H.X., M.W., E.S., E.N., C.X., B.H., D.L.M., J.A.M.); and Lilly Research Laboratories, Eli Lilly and Company, Alcobendas, Spain (L.P.).
authors.forename: Lourdes
authors.initials: L
authors.lastname: Prieto
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana (C.C.F., D.A.S., Y.T., A.Q., H.X., M.W., E.S., E.N., C.X., B.H., D.L.M., J.A.M.); and Lilly Research Laboratories, Eli Lilly and Company, Alcobendas, Spain (L.P.).
authors.forename: David L
authors.initials: DL
authors.lastname: McKinzie
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana (C.C.F., D.A.S., Y.T., A.Q., H.X., M.W., E.S., E.N., C.X., B.H., D.L.M., J.A.M.); and Lilly Research Laboratories, Eli Lilly and Company, Alcobendas, Spain (L.P.).
authors.forename: James A
authors.initials: JA
authors.lastname: Monn
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D001643:Bridged Bicyclo Compounds / Q000378:metabolism / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D054333:Drug Partial Agonism; D018690:Excitatory Amino Acid Agonists / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists* / Q000378:metabolism; D057170:Translational Research, Biomedical; D014230:Triazoles / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D001643:Bridged Bicyclo Compounds; D018690:Excitatory Amino Acid Agonists; C000603803:LY2812223; D018094:Receptors, Metabotropic Glutamate; D014230:Triazoles; C108822:metabotropic glutamate receptor 2