Discovery of VU6081679, a Novel Positive Allosteric Modulator of Metabotropic Glutamate Receptor 8 with Efficacy in a Preclinical Model of Parkinson’s Disease
High Resolution Image Download MS PowerPoint Slide Herein, we report a potent, CNS penetrant, orally bioavailable metabotropic glutamate receptor subtype 8 (mGlu 8 ) positive allosteric modulator (PAM), VU6081679, that shows robust efficacy in a rodent model of Parkinson’s disease. A high-throughput screening effort and subsequent structure–activity relationship study led to the discovery of VU6081679, an mGlu 8 -preferring PAM with good potency at rat, mouse, and human mGlu 8 . Molecular docking into a published cryo-EM structure supports binding in an allosteric pocket at the extracellular TM6/TM7 dimer interface. VU6081679 displays a favorable rodent DMPK profile and demonstrates robust efficacy in a haloperidol-induced catalepsy model of Parkinson’s disease in both rats and mice. Additional studies conducted in mGlu 8 knockout mice confirmed that the observed efficacy is mGlu 8 -mediated.
Authors
- Alice L. Rodriguez (ORCID: https://orcid.org/0000-0002-5244-5103)
- Kayla J. Temple (ORCID: https://orcid.org/0000-0001-5290-574X)
- Allie Han
- Hyekyung P. Cho (ORCID: https://orcid.org/0000-0001-5393-2600)
- Darren W. Engers (ORCID: https://orcid.org/0000-0002-3633-3072)
- Katherine E. Crocker
- Snehal Sant (ORCID: https://orcid.org/0000-0003-0426-4057)
- Colleen M. Niswender (ORCID: https://orcid.org/0000-0001-6009-8212)
- Aidong Qi
- Carrie K. Jones (ORCID: https://orcid.org/0000-0002-1287-9839)
- Analisa Thompson Gray
- Craig W. Lindsley (ORCID: https://orcid.org/0000-0003-0168-1445)
- Anthony S. Ferranti (ORCID: https://orcid.org/0000-0003-4882-2049)
- Dehui Mi (ORCID: https://orcid.org/0000-0002-8587-2929)
- Sri H. Kethanapalli
- B. A. Brown
- Sichen Chang
- Srinivasan Krishnan
- Alexa E. Richardson
- Li Peng
- Joshua C. Wilkinson
- Emily L. Days
- J A Bauer
- Xia Lei (ORCID: https://orcid.org/0000-0003-3195-7190)
- Olivier Boutaud
- Irene Zagol-Ikapitte
- N. Kithmini Wijesiri (ORCID: https://orcid.org/0000-0003-4581-0448)
Institutions
- Allen Institute for Brain Science (US)
- Vanderbilt University (US)
- Institute of Chemical Biology and Fundamental Medicine (RU)
- Kennedy Center (DK)
- Health Advances (United States) (US)
- Center for Discovery (US)
- Artificial Intelligence in Medicine (Canada) (CA)
Publication Details
- Journal
- ACS Chemical Neuroscience
- Published
- 2026-07-16
- DOI
- https://doi.org/10.1021/acschemneuro.6c00364
- Primary Topic
- Neuroscience and Neuropharmacology Research
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Vanderbilt University
- National Institutes of Health
- JDRF