Discovery of a Selective and CNS Penetrant Negative Allosteric Modulator of Metabotropic Glutamate Receptor Subtype 3 with Antidepressant and Anxiolytic Activity in Rodents

Julie L. Engers, Alice L. Rodriguez, Leah C. Konkol, Ryan D. Morrison, Analisa D. Thompson, Frank W. Byers, Anna L. Blobaum, Sichen Chang, Daryl F. Venable, Matthew T. Loch, Colleen M. Niswender, J. Scott Daniels, Carrie K. Jones, P. Jeffrey Conn, Craig W. Lindsley, Kyle Allen Emmitte

Research output: Contribution to journalArticleResearchpeer-review

25 Citations (Scopus)

Abstract

Previous preclinical work has demonstrated the therapeutic potential of antagonists of the group II metabotropic glutamate receptors (mGlus). Still, compounds that are selective for the individual group II mGlus (mGlu2 and mGlu3) have been scarce. There remains a need for such compounds with the balance of properties suitable for convenient use in a wide array of rodent behavioral studies. We describe here the discovery of a selective mGlu3 NAM 106 (VU0650786) suitable for in vivo work. Compound 106 is a member of a series of 5-aryl-6,7-dihydropyrazolo[1,5-a]pyrazine-4(5H)-one compounds originally identified as a mGlu5 positive allosteric modulator (PAM) chemotype. Its suitability for use in rodent behavioral models has been established by extensive in vivo PK studies, and the behavioral experiments presented here with compound 106 represent the first examples in which an mGlu3 NAM has demonstrated efficacy in models where prior efficacy had previously been noted with nonselective group II antagonists.

Original languageEnglish
Pages (from-to)7485-7500
Number of pages16
JournalJournal of Medicinal Chemistry
Volume58
Issue number18
DOIs
StatePublished - 24 Sep 2015

Fingerprint

Metabotropic Glutamate Receptors
Anti-Anxiety Agents
Antidepressive Agents
Rodentia
Pyrazines
compound 106
metabotropic glutamate receptor 3
Therapeutics
VU0650786

Cite this

Engers, Julie L. ; Rodriguez, Alice L. ; Konkol, Leah C. ; Morrison, Ryan D. ; Thompson, Analisa D. ; Byers, Frank W. ; Blobaum, Anna L. ; Chang, Sichen ; Venable, Daryl F. ; Loch, Matthew T. ; Niswender, Colleen M. ; Daniels, J. Scott ; Jones, Carrie K. ; Conn, P. Jeffrey ; Lindsley, Craig W. ; Emmitte, Kyle Allen. / Discovery of a Selective and CNS Penetrant Negative Allosteric Modulator of Metabotropic Glutamate Receptor Subtype 3 with Antidepressant and Anxiolytic Activity in Rodents. In: Journal of Medicinal Chemistry. 2015 ; Vol. 58, No. 18. pp. 7485-7500.
@article{0bab3839d312488e99607a196358c1b4,
title = "Discovery of a Selective and CNS Penetrant Negative Allosteric Modulator of Metabotropic Glutamate Receptor Subtype 3 with Antidepressant and Anxiolytic Activity in Rodents",
abstract = "Previous preclinical work has demonstrated the therapeutic potential of antagonists of the group II metabotropic glutamate receptors (mGlus). Still, compounds that are selective for the individual group II mGlus (mGlu2 and mGlu3) have been scarce. There remains a need for such compounds with the balance of properties suitable for convenient use in a wide array of rodent behavioral studies. We describe here the discovery of a selective mGlu3 NAM 106 (VU0650786) suitable for in vivo work. Compound 106 is a member of a series of 5-aryl-6,7-dihydropyrazolo[1,5-a]pyrazine-4(5H)-one compounds originally identified as a mGlu5 positive allosteric modulator (PAM) chemotype. Its suitability for use in rodent behavioral models has been established by extensive in vivo PK studies, and the behavioral experiments presented here with compound 106 represent the first examples in which an mGlu3 NAM has demonstrated efficacy in models where prior efficacy had previously been noted with nonselective group II antagonists.",
author = "Engers, {Julie L.} and Rodriguez, {Alice L.} and Konkol, {Leah C.} and Morrison, {Ryan D.} and Thompson, {Analisa D.} and Byers, {Frank W.} and Blobaum, {Anna L.} and Sichen Chang and Venable, {Daryl F.} and Loch, {Matthew T.} and Niswender, {Colleen M.} and Daniels, {J. Scott} and Jones, {Carrie K.} and Conn, {P. Jeffrey} and Lindsley, {Craig W.} and Emmitte, {Kyle Allen}",
year = "2015",
month = "9",
day = "24",
doi = "10.1021/acs.jmedchem.5b01005",
language = "English",
volume = "58",
pages = "7485--7500",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "18",

}

Engers, JL, Rodriguez, AL, Konkol, LC, Morrison, RD, Thompson, AD, Byers, FW, Blobaum, AL, Chang, S, Venable, DF, Loch, MT, Niswender, CM, Daniels, JS, Jones, CK, Conn, PJ, Lindsley, CW & Emmitte, KA 2015, 'Discovery of a Selective and CNS Penetrant Negative Allosteric Modulator of Metabotropic Glutamate Receptor Subtype 3 with Antidepressant and Anxiolytic Activity in Rodents', Journal of Medicinal Chemistry, vol. 58, no. 18, pp. 7485-7500. https://doi.org/10.1021/acs.jmedchem.5b01005

Discovery of a Selective and CNS Penetrant Negative Allosteric Modulator of Metabotropic Glutamate Receptor Subtype 3 with Antidepressant and Anxiolytic Activity in Rodents. / Engers, Julie L.; Rodriguez, Alice L.; Konkol, Leah C.; Morrison, Ryan D.; Thompson, Analisa D.; Byers, Frank W.; Blobaum, Anna L.; Chang, Sichen; Venable, Daryl F.; Loch, Matthew T.; Niswender, Colleen M.; Daniels, J. Scott; Jones, Carrie K.; Conn, P. Jeffrey; Lindsley, Craig W.; Emmitte, Kyle Allen.

In: Journal of Medicinal Chemistry, Vol. 58, No. 18, 24.09.2015, p. 7485-7500.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Discovery of a Selective and CNS Penetrant Negative Allosteric Modulator of Metabotropic Glutamate Receptor Subtype 3 with Antidepressant and Anxiolytic Activity in Rodents

AU - Engers, Julie L.

AU - Rodriguez, Alice L.

AU - Konkol, Leah C.

AU - Morrison, Ryan D.

AU - Thompson, Analisa D.

AU - Byers, Frank W.

AU - Blobaum, Anna L.

AU - Chang, Sichen

AU - Venable, Daryl F.

AU - Loch, Matthew T.

AU - Niswender, Colleen M.

AU - Daniels, J. Scott

AU - Jones, Carrie K.

AU - Conn, P. Jeffrey

AU - Lindsley, Craig W.

AU - Emmitte, Kyle Allen

PY - 2015/9/24

Y1 - 2015/9/24

N2 - Previous preclinical work has demonstrated the therapeutic potential of antagonists of the group II metabotropic glutamate receptors (mGlus). Still, compounds that are selective for the individual group II mGlus (mGlu2 and mGlu3) have been scarce. There remains a need for such compounds with the balance of properties suitable for convenient use in a wide array of rodent behavioral studies. We describe here the discovery of a selective mGlu3 NAM 106 (VU0650786) suitable for in vivo work. Compound 106 is a member of a series of 5-aryl-6,7-dihydropyrazolo[1,5-a]pyrazine-4(5H)-one compounds originally identified as a mGlu5 positive allosteric modulator (PAM) chemotype. Its suitability for use in rodent behavioral models has been established by extensive in vivo PK studies, and the behavioral experiments presented here with compound 106 represent the first examples in which an mGlu3 NAM has demonstrated efficacy in models where prior efficacy had previously been noted with nonselective group II antagonists.

AB - Previous preclinical work has demonstrated the therapeutic potential of antagonists of the group II metabotropic glutamate receptors (mGlus). Still, compounds that are selective for the individual group II mGlus (mGlu2 and mGlu3) have been scarce. There remains a need for such compounds with the balance of properties suitable for convenient use in a wide array of rodent behavioral studies. We describe here the discovery of a selective mGlu3 NAM 106 (VU0650786) suitable for in vivo work. Compound 106 is a member of a series of 5-aryl-6,7-dihydropyrazolo[1,5-a]pyrazine-4(5H)-one compounds originally identified as a mGlu5 positive allosteric modulator (PAM) chemotype. Its suitability for use in rodent behavioral models has been established by extensive in vivo PK studies, and the behavioral experiments presented here with compound 106 represent the first examples in which an mGlu3 NAM has demonstrated efficacy in models where prior efficacy had previously been noted with nonselective group II antagonists.

UR - http://www.scopus.com/inward/record.url?scp=84942279943&partnerID=8YFLogxK

U2 - 10.1021/acs.jmedchem.5b01005

DO - 10.1021/acs.jmedchem.5b01005

M3 - Article

VL - 58

SP - 7485

EP - 7500

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 18

ER -