title: Comparative Effects of LY3020371, a Potent and Selective Metabotropic Glutamate (mGlu) 2/3 Receptor Antagonist, and Ketamine, a NoncompetitiveN-Methyl-d-Aspartate Receptor Antagonist in Rodents: Evidence Supporting the Use of mGlu2/3 Antagonists, for the Treatment of Depression.
abstract: The ability of theN-methyl-d-aspartate receptor antagonist ketamine to alleviate symptoms in patients suffering from treatment-resistant depression (TRD) is well documented. In this paper, we directly compare in vivo biologic responses in rodents elicited by a recently discovered metabotropic glutamate (mGlu) 2/3 receptor antagonist 2-amino-3-[(3,4-difluorophenyl)sulfanylmethyl]-4-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY3020371) with those produced by ketamine. Both LY3020371 and ketamine increased the number of spontaneously active dopamine cells in the ventral tegmental area of anesthetized rats, increased O2in the anterior cingulate cortex, promoted wakefulness, enhanced the efflux of biogenic amines in the prefrontal cortex, and produced antidepressant-related behavioral effects in rodent models. The ability of LY3020371 to produce antidepressant-like effects in the forced-swim assay in rats was associated with cerebrospinal fluid (CSF) drug levels that matched concentrations required for functional antagonist activity in native rat brain tissue preparations. Metabolomic pathway analyses from analytes recovered from rat CSF and hippocampus demonstrated that both LY3020371 and ketamine activated common pathways involving GRIA2 and ADORA1. A diester analog of LY3020371 [bis(((isopropoxycarbonyl)oxy)-methyl) (1S,2R,3S,4S,5R,6R)-2-amino-3-(((3,4-difluorophenyl)thio)methyl)-4-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylate (LY3027788)] was an effective oral prodrug; when given orally, it recapitulated effects of intravenous doses of LY3020371 in the forced-swim and wake-promotion assays, and augmented the antidepressant-like effects of fluoxetine or citalopram without altering plasma or brain levels of these compounds. The broad overlap of biologic responses produced by LY3020371 and ketamine supports the hypothesis that mGlu2/3 receptor blockade might be a novel therapeutic approach for the treatment of TRD patients. LY3020371 and LY3027788 represent molecules that are ready for clinical tests of this hypothesis.
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN (J.M.W., C.O., X.L., L.R.-K., K.R., W.H.A., A.N., V.V.T., M.-S.K., J.T.C., R.L., S.C.S., C.H.M., P.L.O., S.S., J.A.M.); and Lilly Research Laboratories, Eli Lilly and Company, Windlesham, Surrey, United Kingdom (S.N.M., K.A.W., G.C., G.G., J.L., B.J.E.) jwitkin@lilly.com mitchell_stephen@lilly.com.
authors.forename: J M
authors.initials: JM
authors.lastname: Witkin
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN (J.M.W., C.O., X.L., L.R.-K., K.R., W.H.A., A.N., V.V.T., M.-S.K., J.T.C., R.L., S.C.S., C.H.M., P.L.O., S.S., J.A.M.); and Lilly Research Laboratories, Eli Lilly and Company, Windlesham, Surrey, United Kingdom (S.N.M., K.A.W., G.C., G.G., J.L., B.J.E.) jwitkin@lilly.com mitchell_stephen@lilly.com.
authors.forename: S N
authors.initials: SN
authors.lastname: Mitchell
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN (J.M.W., C.O., X.L., L.R.-K., K.R., W.H.A., A.N., V.V.T., M.-S.K., J.T.C., R.L., S.C.S., C.H.M., P.L.O., S.S., J.A.M.); and Lilly Research Laboratories, Eli Lilly and Company, Windlesham, Surrey, United Kingdom (S.N.M., K.A.W., G.C., G.G., J.L., B.J.E.).
authors.forename: K A
authors.initials: KA
authors.lastname: Wafford
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN (J.M.W., C.O., X.L., L.R.-K., K.R., W.H.A., A.N., V.V.T., M.-S.K., J.T.C., R.L., S.C.S., C.H.M., P.L.O., S.S., J.A.M.); and Lilly Research Laboratories, Eli Lilly and Company, Windlesham, Surrey, United Kingdom (S.N.M., K.A.W., G.C., G.G., J.L., B.J.E.).
authors.forename: G
authors.initials: G
authors.lastname: Carter
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN (J.M.W., C.O., X.L., L.R.-K., K.R., W.H.A., A.N., V.V.T., M.-S.K., J.T.C., R.L., S.C.S., C.H.M., P.L.O., S.S., J.A.M.); and Lilly Research Laboratories, Eli Lilly and Company, Windlesham, Surrey, United Kingdom (S.N.M., K.A.W., G.C., G.G., J.L., B.J.E.).
authors.forename: G
authors.initials: G
authors.lastname: Gilmour
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN (J.M.W., C.O., X.L., L.R.-K., K.R., W.H.A., A.N., V.V.T., M.-S.K., J.T.C., R.L., S.C.S., C.H.M., P.L.O., S.S., J.A.M.); and Lilly Research Laboratories, Eli Lilly and Company, Windlesham, Surrey, United Kingdom (S.N.M., K.A.W., G.C., G.G., J.L., B.J.E.).
authors.forename: J
authors.initials: J
authors.lastname: Li
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN (J.M.W., C.O., X.L., L.R.-K., K.R., W.H.A., A.N., V.V.T., M.-S.K., J.T.C., R.L., S.C.S., C.H.M., P.L.O., S.S., J.A.M.); and Lilly Research Laboratories, Eli Lilly and Company, Windlesham, Surrey, United Kingdom (S.N.M., K.A.W., G.C., G.G., J.L., B.J.E.).
authors.forename: B J
authors.initials: BJ
authors.lastname: Eastwood
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN (J.M.W., C.O., X.L., L.R.-K., K.R., W.H.A., A.N., V.V.T., M.-S.K., J.T.C., R.L., S.C.S., C.H.M., P.L.O., S.S., J.A.M.); and Lilly Research Laboratories, Eli Lilly and Company, Windlesham, Surrey, United Kingdom (S.N.M., K.A.W., G.C., G.G., J.L., B.J.E.).
authors.forename: C
authors.initials: C
authors.lastname: Overshiner
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN (J.M.W., C.O., X.L., L.R.-K., K.R., W.H.A., A.N., V.V.T., M.-S.K., J.T.C., R.L., S.C.S., C.H.M., P.L.O., S.S., J.A.M.); and Lilly Research Laboratories, Eli Lilly and Company, Windlesham, Surrey, United Kingdom (S.N.M., K.A.W., G.C., G.G., J.L., B.J.E.).
authors.forename: X
authors.initials: X
authors.lastname: Li
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN (J.M.W., C.O., X.L., L.R.-K., K.R., W.H.A., A.N., V.V.T., M.-S.K., J.T.C., R.L., S.C.S., C.H.M., P.L.O., S.S., J.A.M.); and Lilly Research Laboratories, Eli Lilly and Company, Windlesham, Surrey, United Kingdom (S.N.M., K.A.W., G.C., G.G., J.L., B.J.E.).
authors.forename: L
authors.initials: L
authors.lastname: Rorick-Kehn
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN (J.M.W., C.O., X.L., L.R.-K., K.R., W.H.A., A.N., V.V.T., M.-S.K., J.T.C., R.L., S.C.S., C.H.M., P.L.O., S.S., J.A.M.); and Lilly Research Laboratories, Eli Lilly and Company, Windlesham, Surrey, United Kingdom (S.N.M., K.A.W., G.C., G.G., J.L., B.J.E.).
authors.forename: K
authors.initials: K
authors.lastname: Rasmussen
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN (J.M.W., C.O., X.L., L.R.-K., K.R., W.H.A., A.N., V.V.T., M.-S.K., J.T.C., R.L., S.C.S., C.H.M., P.L.O., S.S., J.A.M.); and Lilly Research Laboratories, Eli Lilly and Company, Windlesham, Surrey, United Kingdom (S.N.M., K.A.W., G.C., G.G., J.L., B.J.E.).
authors.forename: W H
authors.initials: WH
authors.lastname: Anderson
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN (J.M.W., C.O., X.L., L.R.-K., K.R., W.H.A., A.N., V.V.T., M.-S.K., J.T.C., R.L., S.C.S., C.H.M., P.L.O., S.S., J.A.M.); and Lilly Research Laboratories, Eli Lilly and Company, Windlesham, Surrey, United Kingdom (S.N.M., K.A.W., G.C., G.G., J.L., B.J.E.).
authors.forename: A
authors.initials: A
authors.lastname: Nikolayev
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN (J.M.W., C.O., X.L., L.R.-K., K.R., W.H.A., A.N., V.V.T., M.-S.K., J.T.C., R.L., S.C.S., C.H.M., P.L.O., S.S., J.A.M.); and Lilly Research Laboratories, Eli Lilly and Company, Windlesham, Surrey, United Kingdom (S.N.M., K.A.W., G.C., G.G., J.L., B.J.E.).
authors.forename: V V
authors.initials: VV
authors.lastname: Tolstikov
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN (J.M.W., C.O., X.L., L.R.-K., K.R., W.H.A., A.N., V.V.T., M.-S.K., J.T.C., R.L., S.C.S., C.H.M., P.L.O., S.S., J.A.M.); and Lilly Research Laboratories, Eli Lilly and Company, Windlesham, Surrey, United Kingdom (S.N.M., K.A.W., G.C., G.G., J.L., B.J.E.).
authors.forename: M-S
authors.initials: MS
authors.lastname: Kuo
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN (J.M.W., C.O., X.L., L.R.-K., K.R., W.H.A., A.N., V.V.T., M.-S.K., J.T.C., R.L., S.C.S., C.H.M., P.L.O., S.S., J.A.M.); and Lilly Research Laboratories, Eli Lilly and Company, Windlesham, Surrey, United Kingdom (S.N.M., K.A.W., G.C., G.G., J.L., B.J.E.).
authors.forename: J T
authors.initials: JT
authors.lastname: Catlow
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN (J.M.W., C.O., X.L., L.R.-K., K.R., W.H.A., A.N., V.V.T., M.-S.K., J.T.C., R.L., S.C.S., C.H.M., P.L.O., S.S., J.A.M.); and Lilly Research Laboratories, Eli Lilly and Company, Windlesham, Surrey, United Kingdom (S.N.M., K.A.W., G.C., G.G., J.L., B.J.E.).
authors.forename: R
authors.initials: R
authors.lastname: Li
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN (J.M.W., C.O., X.L., L.R.-K., K.R., W.H.A., A.N., V.V.T., M.-S.K., J.T.C., R.L., S.C.S., C.H.M., P.L.O., S.S., J.A.M.); and Lilly Research Laboratories, Eli Lilly and Company, Windlesham, Surrey, United Kingdom (S.N.M., K.A.W., G.C., G.G., J.L., B.J.E.).
authors.forename: S C
authors.initials: SC
authors.lastname: Smith
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN (J.M.W., C.O., X.L., L.R.-K., K.R., W.H.A., A.N., V.V.T., M.-S.K., J.T.C., R.L., S.C.S., C.H.M., P.L.O., S.S., J.A.M.); and Lilly Research Laboratories, Eli Lilly and Company, Windlesham, Surrey, United Kingdom (S.N.M., K.A.W., G.C., G.G., J.L., B.J.E.).
authors.forename: C H
authors.initials: CH
authors.lastname: Mitch
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN (J.M.W., C.O., X.L., L.R.-K., K.R., W.H.A., A.N., V.V.T., M.-S.K., J.T.C., R.L., S.C.S., C.H.M., P.L.O., S.S., J.A.M.); and Lilly Research Laboratories, Eli Lilly and Company, Windlesham, Surrey, United Kingdom (S.N.M., K.A.W., G.C., G.G., J.L., B.J.E.).
authors.forename: P L
authors.initials: PL
authors.lastname: Ornstein
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN (J.M.W., C.O., X.L., L.R.-K., K.R., W.H.A., A.N., V.V.T., M.-S.K., J.T.C., R.L., S.C.S., C.H.M., P.L.O., S.S., J.A.M.); and Lilly Research Laboratories, Eli Lilly and Company, Windlesham, Surrey, United Kingdom (S.N.M., K.A.W., G.C., G.G., J.L., B.J.E.).
authors.forename: S
authors.initials: S
authors.lastname: Swanson
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN (J.M.W., C.O., X.L., L.R.-K., K.R., W.H.A., A.N., V.V.T., M.-S.K., J.T.C., R.L., S.C.S., C.H.M., P.L.O., S.S., J.A.M.); and Lilly Research Laboratories, Eli Lilly and Company, Windlesham, Surrey, United Kingdom (S.N.M., K.A.W., G.C., G.G., J.L., B.J.E.).
authors.forename: J A
authors.initials: JA
authors.lastname: Monn
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology / Q000627:therapeutic use*; D003863:Depression / Q000188:drug therapy / Q000378:metabolism / Q000523:psychology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D007649:Ketamine / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D000928:Antidepressive Agents; D018691:Excitatory Amino Acid Antagonists; D018094:Receptors, Metabotropic Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; C108822:metabotropic glutamate receptor 2; C102718:metabotropic glutamate receptor 3; D007649:Ketamine