Discovery of a Selective and CNS Penetrant Negative Allosteric Modulator of Metabotropic Glutamate Receptor Subtype 3 with Antidepressant and Anxiolytic Activity in Rodents.
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.
Vanderbilt Center for Neuroscience Drug Discovery, Department of Pharmacology, Vanderbilt University Medical Center , Nashville, Tennessee 37232, United States.
Julie L
JL
Engers
Vanderbilt Center for Neuroscience Drug Discovery, Department of Pharmacology, Vanderbilt University Medical Center , Nashville, Tennessee 37232, United States.
Alice L
AL
Rodriguez
Vanderbilt Center for Neuroscience Drug Discovery, Department of Pharmacology, Vanderbilt University Medical Center , Nashville, Tennessee 37232, United States.
Leah C
LC
Konkol
Vanderbilt Center for Neuroscience Drug Discovery, Department of Pharmacology, Vanderbilt University Medical Center , Nashville, Tennessee 37232, United States.
Ryan D
RD
Morrison
Vanderbilt Center for Neuroscience Drug Discovery, Department of Pharmacology, Vanderbilt University Medical Center , Nashville, Tennessee 37232, United States.
Analisa D
AD
Thompson
Vanderbilt Center for Neuroscience Drug Discovery, Department of Pharmacology, Vanderbilt University Medical Center , Nashville, Tennessee 37232, United States.
Frank W
FW
Byers
Vanderbilt Center for Neuroscience Drug Discovery, Department of Pharmacology, Vanderbilt University Medical Center , Nashville, Tennessee 37232, United States.
Anna L
AL
Blobaum
Vanderbilt Center for Neuroscience Drug Discovery, Department of Pharmacology, Vanderbilt University Medical Center , Nashville, Tennessee 37232, United States.
Sichen
S
Chang
Vanderbilt Center for Neuroscience Drug Discovery, Department of Pharmacology, Vanderbilt University Medical Center , Nashville, Tennessee 37232, United States.
Daryl F
DF
Venable
Vanderbilt Center for Neuroscience Drug Discovery, Department of Pharmacology, Vanderbilt University Medical Center , Nashville, Tennessee 37232, United States.
Matthew T
MT
Loch
Vanderbilt Center for Neuroscience Drug Discovery, Department of Pharmacology, Vanderbilt University Medical Center , Nashville, Tennessee 37232, United States.
Colleen M
CM
Niswender
Vanderbilt Center for Neuroscience Drug Discovery, Department of Pharmacology, Vanderbilt University Medical Center , Nashville, Tennessee 37232, United States.
J Scott
JS
Daniels
Vanderbilt Center for Neuroscience Drug Discovery, Department of Pharmacology, Vanderbilt University Medical Center , Nashville, Tennessee 37232, United States.
Carrie K
CK
Jones
Vanderbilt Center for Neuroscience Drug Discovery, Department of Pharmacology, Vanderbilt University Medical Center , Nashville, Tennessee 37232, United States.
P Jeffrey
PJ
Conn
Vanderbilt Center for Neuroscience Drug Discovery, Department of Pharmacology, Vanderbilt University Medical Center , Nashville, Tennessee 37232, United States.|Department of Chemistry, Vanderbilt University , Nashville, Tennessee 37232, United States.
Craig W
CW
Lindsley
Vanderbilt Center for Neuroscience Drug Discovery, Department of Pharmacology, Vanderbilt University Medical Center , Nashville, Tennessee 37232, United States.|Department of Chemistry, Vanderbilt University , Nashville, Tennessee 37232, United States.
Kyle A
KA
Emmitte
D000494:Allosteric Regulation; D000818:Animals; D014151:Anti-Anxiety Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D000928:Antidepressive Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D001921:Brain / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D004285:Dogs; D006574:Heterocyclic Compounds, 2-Ring / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D061985:Madin Darby Canine Kidney Cells; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D010539:Permeability; D011725:Pyridines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D014151:Anti-Anxiety Agents; D000928:Antidepressive Agents; D006574:Heterocyclic Compounds, 2-Ring; D011725:Pyridines; D018094:Receptors, Metabotropic Glutamate; C000603801:VU0650786; C102718:metabotropic glutamate receptor 3; D002118:Calcium