CVN636 potentiates orthosteric agonist responses selectively at mGlu7/7 homodimers
- 1Department of Psychiatry, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA
Abstract
The metabotropic glutamate receptor 7 (mGlu7) is an emerging therapeutic target for central nervous system disorders, but progress has been limited by a lack of selective pharmacological tools. CVN636 was recently reported as a potent and selective allosteric agonist of this receptor, capable of receptor activation in the absence of glutamate, with demonstrated efficacy in a rodent model of alcohol use disorder. Here, using complementary bioluminescence resonance energy transfer-based assays that measure both downstream signaling and G protein recruitment, we show that CVN636 does not activate the receptor on its own. Instead, CVN636 acts as a positive allosteric modulator that enhances the potency and efficacy of orthosteric agonist responses, including those of glutamate, in an agonist-dependent manner. Blockade of orthosteric agonist binding with a competitive antagonist abolished CVN636 activity, consistent with this mechanism. Furthermore, using an assay that distinguishes signaling from defined receptor dimers, we find that CVN636 activity is selective for mGlu7/7 homodimers and does not extend to any mGlu7-containing heterodimer tested. Thus, in our assay system CVN636 is an mGlu7/7 homodimer-selective positive allosteric modulator of this receptor, suggesting that its in vivo actions likely stem from action at these homomers.
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BibTeX
@misc{lin2026cvn636,
title = {{CVN636 potentiates orthosteric agonist responses selectively at mGlu7/7 homodimers}},
author = {X. Lin and C. M. Niswender and W. B. Asher and J. A. Javitch},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.17.759826},
url = {https://www.biorxiv.org/content/10.64898/2026.10.17.759826v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - CVN636 potentiates orthosteric agonist responses selectively at mGlu7/7 homodimers
AU - X. Lin
AU - C. M. Niswender
AU - W. B. Asher
AU - J. A. Javitch
PY - 2026
DA - 2026/10/17
PB - bioRxiv
DO - 10.64898/2026.10.17.759826
UR - https://www.biorxiv.org/content/10.64898/2026.10.17.759826v1
AB - The metabotropic glutamate receptor 7 (mGlu7) is an emerging therapeutic target for central nervous system disorders, but progress has been limited by a lack of selective pharmacological tools. CVN636 was recently reported as a potent and selective allosteric agonist of this receptor, capable of receptor activation in the absence of glutamate, with demonstrated efficacy in a rodent model of alcohol use disorder. Here, using complementary bioluminescence resonance energy transfer-based assays that measure both downstream signaling and G protein recruitment, we show that CVN636 does not activate the receptor on its own. Instead, CVN636 acts as a positive allosteric modulator that enhances the potency and efficacy of orthosteric agonist responses, including those of glutamate, in an agonist-dependent manner. Blockade of orthosteric agonist binding with a competitive antagonist abolished CVN636 activity, consistent with this mechanism. Furthermore, using an assay that distinguishes signaling from defined receptor dimers, we find that CVN636 activity is selective for mGlu7/7 homodimers and does not extend to any mGlu7-containing heterodimer tested. Thus, in our assay system CVN636 is an mGlu7/7 homodimer-selective positive allosteric modulator of this receptor, suggesting that its in vivo actions likely stem from action at these homomers.
ER -