Isoxazolo[3,4-d]pyridazinones positively modulate the metabotropic glutamate subtypes 2 and 4

Christina Gates; Donald S. Backos; Philip Reigan; Hye Jin Kang; Chris Koerner; Joseph Mirzaei; N. R. Natale

doi:10.1016/j.bmc.2018.08.012

Isoxazolo[3,4-d]pyridazinones positively modulate the metabotropic glutamate subtypes 2 and 4

Christina Gates, Donald S. Backos, Philip Reigan, Hye Jin Kang, Chris Koerner, Joseph Mirzaei, N. R. Natale

Research output: Contribution to journal › Article › peer-review

2 Scopus citations

Abstract

Isoxazolo[3,4-d] pyridazinones ([3,4-d]s) are selective positive modulators of the metabotropic glutamate receptors (mGluRs) subtypes 2 and 4, with no functional cross reactivity at mGluR _1a , mGLuR ₅ or mGluR ₈ . Modest binding for two of the [3,4-d]s is observed at the allosteric fenobam mGluR ₅ site, but not sufficient to translate into a functional effect. The structure activity relationship (SAR) for mGluR ₂ and mGluR ₄ are distinct: the compounds which select for mGluR ₂ all contain fluorine on the N-6 aryl group. Furthermore, the [3,4-d]s in this study showed no significant binding at inhibitory GABA _A nor excitatory NMDA receptors, and previously we had disclosed that they lack significant activity at the System Xc-Antiporter. A homology model based on Conn's mGluR ₁ crystal structure was examined, and suggested explanations for a preference for allosteric over orthosteric binding, subtype selectivity, and suggested avenues for optimization of efficacy as a reasonable working hypothesis.

Original language	English
Pages (from-to)	4797-4803
Number of pages	7
Journal	Bioorganic and Medicinal Chemistry
Volume	26
Issue number	17
DOIs	https://doi.org/10.1016/j.bmc.2018.08.012
State	Published - Sep 15 2018

Funding

Testing data was generously provided by the National Institute of Mental Health’s Psychoactive Drug Screening Program, Contract # HHSN-271-2013-00017-C (NIMH PDSP). The NIMH PDSP is Directed by Bryan L. Roth, MD, PhD, at the University of North Carolina at Chapel Hill and Project Officer, Jamie Driscoll, at NIMH, Bethesda MD, USA. The authors thank the Center for Structural and Functional Neuroscience (CSFN) for a pilot grant under NINDS P20 RR015583, the ALSAM foundation Skaggs Scholars Program Grant (NRN, DSB and PR), CBSD CoBRE grant P20GM103546 (NN), and the University of Montana for the award of a small grant from the University Grants Program. Computational modeling studies were conducted at the University of Colorado Computational Chemistry and Biology Core Facility, which is funded in part by NIH/NCATS UL1 TR001082. We acknowledge Trideep Rajale for technical assistance.

Funder number
P20GM103546
HHSN-271-2013-00017-C
P20 RR015583
UL1TR001082

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title = "Isoxazolo[3,4-d]pyridazinones positively modulate the metabotropic glutamate subtypes 2 and 4",

abstract = " Isoxazolo[3,4-d] pyridazinones ([3,4-d]s) are selective positive modulators of the metabotropic glutamate receptors (mGluRs) subtypes 2 and 4, with no functional cross reactivity at mGluR 1a , mGLuR 5 or mGluR 8 . Modest binding for two of the [3,4-d]s is observed at the allosteric fenobam mGluR 5 site, but not sufficient to translate into a functional effect. The structure activity relationship (SAR) for mGluR 2 and mGluR 4 are distinct: the compounds which select for mGluR 2 all contain fluorine on the N-6 aryl group. Furthermore, the [3,4-d]s in this study showed no significant binding at inhibitory GABA A nor excitatory NMDA receptors, and previously we had disclosed that they lack significant activity at the System Xc-Antiporter. A homology model based on Conn's mGluR 1 crystal structure was examined, and suggested explanations for a preference for allosteric over orthosteric binding, subtype selectivity, and suggested avenues for optimization of efficacy as a reasonable working hypothesis.",

author = "Christina Gates and Backos, \{Donald S.\} and Philip Reigan and Kang, \{Hye Jin\} and Chris Koerner and Joseph Mirzaei and Natale, \{N. R.\}",

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doi = "10.1016/j.bmc.2018.08.012",

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AU - Gates, Christina

AU - Backos, Donald S.

AU - Reigan, Philip

AU - Kang, Hye Jin

AU - Koerner, Chris

AU - Mirzaei, Joseph

AU - Natale, N. R.

PY - 2018/9/15

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N2 - Isoxazolo[3,4-d] pyridazinones ([3,4-d]s) are selective positive modulators of the metabotropic glutamate receptors (mGluRs) subtypes 2 and 4, with no functional cross reactivity at mGluR 1a , mGLuR 5 or mGluR 8 . Modest binding for two of the [3,4-d]s is observed at the allosteric fenobam mGluR 5 site, but not sufficient to translate into a functional effect. The structure activity relationship (SAR) for mGluR 2 and mGluR 4 are distinct: the compounds which select for mGluR 2 all contain fluorine on the N-6 aryl group. Furthermore, the [3,4-d]s in this study showed no significant binding at inhibitory GABA A nor excitatory NMDA receptors, and previously we had disclosed that they lack significant activity at the System Xc-Antiporter. A homology model based on Conn's mGluR 1 crystal structure was examined, and suggested explanations for a preference for allosteric over orthosteric binding, subtype selectivity, and suggested avenues for optimization of efficacy as a reasonable working hypothesis.

AB - Isoxazolo[3,4-d] pyridazinones ([3,4-d]s) are selective positive modulators of the metabotropic glutamate receptors (mGluRs) subtypes 2 and 4, with no functional cross reactivity at mGluR 1a , mGLuR 5 or mGluR 8 . Modest binding for two of the [3,4-d]s is observed at the allosteric fenobam mGluR 5 site, but not sufficient to translate into a functional effect. The structure activity relationship (SAR) for mGluR 2 and mGluR 4 are distinct: the compounds which select for mGluR 2 all contain fluorine on the N-6 aryl group. Furthermore, the [3,4-d]s in this study showed no significant binding at inhibitory GABA A nor excitatory NMDA receptors, and previously we had disclosed that they lack significant activity at the System Xc-Antiporter. A homology model based on Conn's mGluR 1 crystal structure was examined, and suggested explanations for a preference for allosteric over orthosteric binding, subtype selectivity, and suggested avenues for optimization of efficacy as a reasonable working hypothesis.

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JO - Bioorganic and Medicinal Chemistry

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IS - 17

ER -

Isoxazolo[3,4-d]pyridazinones positively modulate the metabotropic glutamate subtypes 2 and 4

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