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 journalArticlepeer-review

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 languageEnglish
Pages (from-to)4797-4803
Number of pages7
JournalBioorganic and Medicinal Chemistry
Volume26
Issue number17
DOIs
StatePublished - Sep 15 2018

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