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Your search keyword '"Tripp, Allie E."' showing total 2 results
Start Over Author "Tripp, Allie E." Topic antidepressive agents
2 results on '"Tripp, Allie E."'

1. Discovery of (1S,2R,3S,4S,5R,6R)-2-Amino-3-[(3,4-difluorophenyl)sulfanylmethyl]-4-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic Acid Hydrochloride (LY3020371·HCl): A Potent, Metabotropic Glutamate 2/3 Receptor Antagonist with Antidepressant-Like Activity.

Author

Chappell MD, Li R, Smith SC, Dressman BA, Tromiczak EG, Tripp AE, Blanco MJ, Vetman T, Quimby SJ, Matt J, Britton TC, Fivush AM, Schkeryantz JM, Mayhugh D, Erickson JA, Bures MG, Jaramillo C, Carpintero M, Diego JE, Barberis M, Garcia-Cerrada S, Soriano JF, Antonysamy S, Atwell S, MacEwan I, Condon B, Sougias C, Wang J, Zhang A, Conners K, Groshong C, Wasserman SR, Koss JW, Witkin JM, Li X, Overshiner C, Wafford KA, Seidel W, Wang XS, Heinz BA, Swanson S, Catlow JT, Bedwell DW, Monn JA, Mitch CH, and Ornstein PL

Subjects
Animals, Antidepressive Agents chemical synthesis, Antidepressive Agents chemistry, Brain drug effects, Cyclohexanes chemical synthesis, Cyclohexanes chemistry, Cyclohexanes pharmacology, Dose-Response Relationship, Drug, Humans, Male, Mice, Mice, Inbred Strains, Models, Molecular, Molecular Structure, Motor Activity drug effects, Receptors, Metabotropic Glutamate chemistry, Receptors, Metabotropic Glutamate isolation & purification, Structure-Activity Relationship, Swimming, Antidepressive Agents pharmacology, Behavior, Animal drug effects, Drug Discovery, Receptors, Metabotropic Glutamate antagonists & inhibitors
Abstract

As part of our ongoing efforts to identify novel ligands for the metabotropic glutamate 2 and 3 (mGlu 2/3 ) receptors, we have incorporated substitution at the C3 and C4 positions of the (1S,2R,5R,6R)-2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid scaffold to generate mGlu 2/3 antagonists. Exploration of this structure-activity relationship (SAR) led to the identification of (1S,2R,3S,4S,5R,6R)-2-amino-3-[(3,4-difluorophenyl)sulfanylmethyl]-4-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid hydrochloride (LY3020371·HCl, 19f), a potent, selective, and maximally efficacious mGlu 2/3 antagonist. Further characterization of compound 19f binding to the human metabotropic 2 glutamate (hmGlu 2 ) site was established by cocrystallization of this molecule with the amino terminal domain (ATD) of the hmGlu 2 receptor protein. The resulting cocrystal structure revealed the specific ligand-protein interactions, which likely explain the high affinity of 19f for this site and support its functional mGlu 2 antagonist pharmacology. Further characterization of 19f in vivo demonstrated an antidepressant-like signature in the mouse forced-swim test (mFST) assay when brain levels of this compound exceeded the cellular mGlu 2 IC 50 value.

Published
2016
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2. Novel bicyclo[3.1.0]hexane analogs as antagonists of metabotropic glutamate 2/3 receptors for the treatment of depression.

Author

Dressman BA, Tromiczak EG, Chappell MD, Tripp AE, Quimby SJ, Vetman T, Fivush AM, Matt J, Jaramillo C, Li R, Khilevich A, Blanco MJ, Smith SC, Carpintero M, de Diego JE, Barberis M, García-Cerrada S, Soriano JF, Schkeryantz JM, Witkin JM, Wafford KA, Seidel W, Britton T, Overshiner CD, Li X, Wang XS, Heinz BA, Catlow JT, Swanson S, Bedwell D, Ornstein PL, and Mitch CH

Subjects
Animals, Antidepressive Agents pharmacokinetics, Bridged Bicyclo Compounds chemistry, Bridged Bicyclo Compounds pharmacokinetics, Bridged Bicyclo Compounds pharmacology, Cell Line, Depressive Disorder, Major metabolism, Dogs, Glutamic Acid pharmacokinetics, Haplorhini, Hexanes chemistry, Hexanes pharmacokinetics, Hexanes pharmacology, Humans, Madin Darby Canine Kidney Cells, Mice, Rats, Receptors, Metabotropic Glutamate metabolism, Antidepressive Agents chemistry, Antidepressive Agents pharmacology, Depressive Disorder, Major drug therapy, Glutamic Acid analogs & derivatives, Glutamic Acid pharmacology, Receptors, Metabotropic Glutamate antagonists & inhibitors
Abstract

Negative modulators of metabotropic glutamate 2 & 3 receptors demonstrate antidepressant-like activity in animal models and hold promise as novel therapeutic agents for the treatment of major depressive disorder. Herein we describe our efforts to prepare and optimize a series of conformationally constrained 3,4-disubstituted bicyclo[3.1.0]hexane glutamic acid analogs as orthosteric (glutamate site) mGlu 2/3 receptor antagonists. This work led to the discovery of a highly potent and efficacious tool compound 18 (hmGlu 2 IC 50 46±14.2nM, hmGlu 3 IC 50 =46.1±36.2nM). Compound 18 showed activity in the mouse forced swim test with a minimal effective dose (MED) of 1mg/kg ip. While in rat EEG studies it exhibited wake promoting effects at 3 and 10mg/kg ip without any significant effects on locomotor activity. Compound 18 thus represents a novel tool molecule for studying the impact of blocking mGlu 2/3 receptors both in vitro and in vivo., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Published
2016
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