Identification of positive allosteric modulators VU0155094 (ML397) and VU0422288 (ML396) reveals new insights into the biology of metabotropic glutamate receptor 7

Nidhi Jalan-Sakrikar, Julie R. Field, Rebecca Klar, Margrith E. Mattmann, Karen J. Gregory, Rocio Zamorano, Darren W. Engers, Sean R. Bollinger, C. David Weaver, Emily L. Days, L. Michelle Lewis, Thomas J. Utley, Miguel Hurtado, Delphine Rigault, Francine Acher, Adam G. Walker, Bruce J. Melancon, Michael R. Wood, Craig W. Lindsley, P. Jeffrey ConnZixiu Xiang, Corey R. Hopkins, Colleen M. Niswender

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

(Figure Presented) Metabotropic glutamate receptor 7 (mGlu7) is a member of the group III mGlu receptors (mGlus), encompassed by mGlu4, mGlu6, mGlu7, and mGlu8. mGlu7 is highly expressed in the presynaptic active zones of both excitatory and inhibitory synapses, and activation of the receptor regulates the release of both glutamate and GABA. mGlu7 is thought to be a relevant therapeutic target for a number of neurological and psychiatric disorders, and polymorphisms in the GRM7 gene have been linked to autism, depression, ADHD, and schizophrenia. Here we report two new pan-group III mGlu positive allosteric modulators, VU0155094 and VU0422288, which show differential activity at the various group III mGlus. Additionally, both compounds show probe dependence when assessed in the presence of distinct orthosteric agonists. By pairing studies of these nonselective compounds with a synapse in the hippocampus that expresses only mGlu7, we have validated activity of these compounds in a native tissue setting. These studies provide proof-of-concept evidence that mGlu7 activity can be modulated by positive allosteric modulation, paving the way for future therapeutics development.

Original languageEnglish (US)
Pages (from-to)1221-1237
Number of pages17
JournalACS Chemical Neuroscience
Volume5
Issue number12
DOIs
StatePublished - Dec 17 2014

Fingerprint

Modulators
Synapses
Autistic Disorder
Nervous System Diseases
Polymorphism
gamma-Aminobutyric Acid
Psychiatry
VU0155094
VU0422288
metabotropic glutamate receptor 7
Glutamic Acid
Hippocampus
Schizophrenia
Genes
Chemical activation
Modulation
Tissue
Depression
Therapeutics

Keywords

  • Allosteric modulator
  • Electrophysiology
  • Hippocampus
  • Metabotropic glutamate receptor

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Cognitive Neuroscience
  • Cell Biology

Cite this

Identification of positive allosteric modulators VU0155094 (ML397) and VU0422288 (ML396) reveals new insights into the biology of metabotropic glutamate receptor 7. / Jalan-Sakrikar, Nidhi; Field, Julie R.; Klar, Rebecca; Mattmann, Margrith E.; Gregory, Karen J.; Zamorano, Rocio; Engers, Darren W.; Bollinger, Sean R.; Weaver, C. David; Days, Emily L.; Lewis, L. Michelle; Utley, Thomas J.; Hurtado, Miguel; Rigault, Delphine; Acher, Francine; Walker, Adam G.; Melancon, Bruce J.; Wood, Michael R.; Lindsley, Craig W.; Conn, P. Jeffrey; Xiang, Zixiu; Hopkins, Corey R.; Niswender, Colleen M.

In: ACS Chemical Neuroscience, Vol. 5, No. 12, 17.12.2014, p. 1221-1237.

Research output: Contribution to journalArticle

Jalan-Sakrikar, N, Field, JR, Klar, R, Mattmann, ME, Gregory, KJ, Zamorano, R, Engers, DW, Bollinger, SR, Weaver, CD, Days, EL, Lewis, LM, Utley, TJ, Hurtado, M, Rigault, D, Acher, F, Walker, AG, Melancon, BJ, Wood, MR, Lindsley, CW, Conn, PJ, Xiang, Z, Hopkins, CR & Niswender, CM 2014, 'Identification of positive allosteric modulators VU0155094 (ML397) and VU0422288 (ML396) reveals new insights into the biology of metabotropic glutamate receptor 7', ACS Chemical Neuroscience, vol. 5, no. 12, pp. 1221-1237. https://doi.org/10.1021/cn500153z
Jalan-Sakrikar, Nidhi ; Field, Julie R. ; Klar, Rebecca ; Mattmann, Margrith E. ; Gregory, Karen J. ; Zamorano, Rocio ; Engers, Darren W. ; Bollinger, Sean R. ; Weaver, C. David ; Days, Emily L. ; Lewis, L. Michelle ; Utley, Thomas J. ; Hurtado, Miguel ; Rigault, Delphine ; Acher, Francine ; Walker, Adam G. ; Melancon, Bruce J. ; Wood, Michael R. ; Lindsley, Craig W. ; Conn, P. Jeffrey ; Xiang, Zixiu ; Hopkins, Corey R. ; Niswender, Colleen M. / Identification of positive allosteric modulators VU0155094 (ML397) and VU0422288 (ML396) reveals new insights into the biology of metabotropic glutamate receptor 7. In: ACS Chemical Neuroscience. 2014 ; Vol. 5, No. 12. pp. 1221-1237.
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AU - Klar, Rebecca

AU - Mattmann, Margrith E.

AU - Gregory, Karen J.

AU - Zamorano, Rocio

AU - Engers, Darren W.

AU - Bollinger, Sean R.

AU - Weaver, C. David

AU - Days, Emily L.

AU - Lewis, L. Michelle

AU - Utley, Thomas J.

AU - Hurtado, Miguel

AU - Rigault, Delphine

AU - Acher, Francine

AU - Walker, Adam G.

AU - Melancon, Bruce J.

AU - Wood, Michael R.

AU - Lindsley, Craig W.

AU - Conn, P. Jeffrey

AU - Xiang, Zixiu

AU - Hopkins, Corey R.

AU - Niswender, Colleen M.

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N2 - (Figure Presented) Metabotropic glutamate receptor 7 (mGlu7) is a member of the group III mGlu receptors (mGlus), encompassed by mGlu4, mGlu6, mGlu7, and mGlu8. mGlu7 is highly expressed in the presynaptic active zones of both excitatory and inhibitory synapses, and activation of the receptor regulates the release of both glutamate and GABA. mGlu7 is thought to be a relevant therapeutic target for a number of neurological and psychiatric disorders, and polymorphisms in the GRM7 gene have been linked to autism, depression, ADHD, and schizophrenia. Here we report two new pan-group III mGlu positive allosteric modulators, VU0155094 and VU0422288, which show differential activity at the various group III mGlus. Additionally, both compounds show probe dependence when assessed in the presence of distinct orthosteric agonists. By pairing studies of these nonselective compounds with a synapse in the hippocampus that expresses only mGlu7, we have validated activity of these compounds in a native tissue setting. These studies provide proof-of-concept evidence that mGlu7 activity can be modulated by positive allosteric modulation, paving the way for future therapeutics development.

AB - (Figure Presented) Metabotropic glutamate receptor 7 (mGlu7) is a member of the group III mGlu receptors (mGlus), encompassed by mGlu4, mGlu6, mGlu7, and mGlu8. mGlu7 is highly expressed in the presynaptic active zones of both excitatory and inhibitory synapses, and activation of the receptor regulates the release of both glutamate and GABA. mGlu7 is thought to be a relevant therapeutic target for a number of neurological and psychiatric disorders, and polymorphisms in the GRM7 gene have been linked to autism, depression, ADHD, and schizophrenia. Here we report two new pan-group III mGlu positive allosteric modulators, VU0155094 and VU0422288, which show differential activity at the various group III mGlus. Additionally, both compounds show probe dependence when assessed in the presence of distinct orthosteric agonists. By pairing studies of these nonselective compounds with a synapse in the hippocampus that expresses only mGlu7, we have validated activity of these compounds in a native tissue setting. These studies provide proof-of-concept evidence that mGlu7 activity can be modulated by positive allosteric modulation, paving the way for future therapeutics development.

KW - Allosteric modulator

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KW - Hippocampus

KW - Metabotropic glutamate receptor

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