Positive allosteric modulators (PAMs) of the group II metabotropic glutamate receptors: Design, synthesis, and evaluation as ex-vivo tool compounds

Yamada, Yousuke; Gilliland, Kristen; Xiang, Zixiu; Haymer, Daniel; Crocker, Katherine E.; Loch, Matthew T.; Schulte, M.; Rodriguez, Alice L.; Niswender, Colleen M.; Conn, P. Jeffrey; Lindsley, Craig W.; Melancon, Bruce J.

doi:10.1016/j.bmcl.2021.128342

Cited by 3 publications

(3 citation statements)

References 26 publications

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“…PAMs have been reported across mGluR subtypes as potentially viable therapeutics for a range of disorders 25,33,62 , but only one so far has been shown to have activity on mGluR3. This compound, VU6023326 ("VU602"), is a recently reported PAM with similar apparent affinity for mGluR2 and mGluR3 63 . It contains two six membered aromatic rings with bulky substituents connected via a short, ethereal linker, showing general similarity to many mGluR PAMs (Fig.…”

Section: Pams Promote Activation and Desensitization With A Bias Towa...mentioning

confidence: 99%

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Structural basis of allosteric modulation of metabotropic glutamate receptor activation and desensitization

Strauss

Gonzalez-Hernandez

Lee

et al. 2023

Preprint

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The metabotropic glutamate receptors (mGluRs) are neuromodulatory family C G protein coupled receptors, which assemble as dimers and allosterically couple extracellular ligand binding domains (LBDs) to transmembrane domains (TMDs) to drive intracellular signaling. Pharmacologically, mGluRs can be targeted either at the LBDs by glutamate and synthetic orthosteric compounds or at the TMDs by allosteric modulators. Despite the potential of allosteric TMD-targeting compounds as therapeutics, an understanding of the functional and structural basis of their effects on mGluRs is limited. Here we use a battery of approaches to dissect the distinct functional and structural effects of orthosteric versus allosteric ligands. We find using electrophysiological and live cell imaging assays that both agonists and positive allosteric modulators (PAMs) can drive activation and desensitization of mGluRs. The effects of PAMs are pleiotropic, including both the ability to boost the maximal response to orthosteric agonists and to serve independently as desensitization-biased agonists across mGluR subtypes. Conformational sensors reveal PAM-driven inter-subunit re-arrangements at both the LBD and TMD. Motivated by this, we determine cryo-electron microscopy structures of mGluR3 in the presence of either an agonist or antagonist alone or in combination with a PAM. These structures reveal PAM-driven re-shaping of intra- and inter-subunit conformations and provide evidence for a rolling TMD dimer interface activation pathway that controls G protein and beta-arrestin coupling.

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Section: Pams Promote Activation and Desensitization With A Bias Towa...mentioning

confidence: 99%

“…Detailed in vitro evaluation of VU602 and structurally related compounds can be found in Yamada et al 63 .…”

Section: Compound Synthesis and Medicinal Chemistrymentioning

confidence: 99%

Structural basis of allosteric modulation of metabotropic glutamate receptor activation and desensitization

Strauss

Gonzalez-Hernandez

Lee

et al. 2023

Preprint

Self Cite

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“…These receptors are activated by a number of positive allosteric modulators (PAMs). Yamada et al reported the total synthesis of some positive allosteric modulators (PAMs) 313 , 316 , 319 , and 322 for mGlu 2 and mGlu 3 receptors, in 2021 [ 87 ]. Starting with butanone derivative 309 , alkylation was performed by employing either – R or S -oxirane derivative 310 to obtain 311 in a 97% yield.…”

Section: Review Of the Literaturementioning

confidence: 99%

Mitsunobu Reaction: A Powerful Tool for the Synthesis of Natural Products: A Review

et al. 2022

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The Mitsunobu reaction plays a vital part in organic chemistry due to its wide synthetic applications. It is considered as a significant reaction for the interconversion of one functional group (alcohol) to another (ester) in the presence of oxidizing agents (azodicarboxylates) and reducing agents (phosphines). It is a renowned stereoselective reaction which inverts the stereochemical configuration of end products. One of the most important applications of the Mitsunobu reaction is its role in the synthesis of natural products. This review article will focus on the contribution of the Mitsunobu reaction towards the total synthesis of natural products, highlighting their biological potential during recent years.

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Structural basis of positive allosteric modulation of metabotropic glutamate receptor activation and internalization

Strauss,

Gonzalez-Hernandez,

Lee

et al. 2024

Nat Commun

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The metabotropic glutamate receptors (mGluRs) are neuromodulatory family C G protein coupled receptors which assemble as dimers and allosterically couple extracellular ligand binding domains (LBDs) to transmembrane domains (TMDs) to drive intracellular signaling. Pharmacologically, mGluRs can be targeted at the LBDs by glutamate and synthetic orthosteric compounds or at the TMDs by allosteric modulators. Despite the potential of allosteric compounds as therapeutics, an understanding of the functional and structural basis of their effects is limited. Here we use multiple approaches to dissect the functional and structural effects of orthosteric versus allosteric ligands. We find, using electrophysiological and live cell imaging assays, that both agonists and positive allosteric modulators (PAMs) can drive activation and internalization of group II and III mGluRs. The effects of PAMs are pleiotropic, boosting the maximal response to orthosteric agonists and serving independently as internalization-biased agonists across mGluR subtypes. Motivated by this and intersubunit FRET analyses, we determine cryo-electron microscopy structures of mGluR3 in the presence of either an agonist or antagonist alone or in combination with a PAM. These structures reveal PAM-driven re-shaping of intra- and inter-subunit conformations and provide evidence for a rolling TMD dimer interface activation pathway that controls G protein and beta-arrestin coupling.

show abstract

Positive allosteric modulators (PAMs) of the group II metabotropic glutamate receptors: Design, synthesis, and evaluation as ex-vivo tool compounds

Cited by 3 publications

References 26 publications

Structural basis of allosteric modulation of metabotropic glutamate receptor activation and desensitization

Structural basis of allosteric modulation of metabotropic glutamate receptor activation and desensitization

Mitsunobu Reaction: A Powerful Tool for the Synthesis of Natural Products: A Review

Structural basis of positive allosteric modulation of metabotropic glutamate receptor activation and internalization

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