Discovery of VU6066098: A Selective and CNS-Penetrant mGlu2 NAM with Robust Antidepressant-, Antipsychotic-, and Procognitive-like Activity in Rodents

  • ACS Chem Neurosci. 2026 Jul 15;17(14):2730-2738. doi: 10.1021/acschemneuro.6c00324.
Jeremy S Coleman  1  2 ,  Rory A Capstick  1  2  3 ,  Sichen Chang  1  2  3 ,  Derek J Rios  1  2  3 ,  Michael Bubser  1  2  3 ,  Analisa D Thompson Gray  1  2  3 ,  Irene Zagol-Ikapitte  1  2  3 ,  Srinivasan Krishnan  1  2  3 ,  Hyekyung P Cho  1  2  3 ,  Alice L Rodriguez  1  2  3 ,  Colleen M Niswender  1  2  4  3  5  6 ,  Olivier Boutaud  1  2  3 ,  Georgina Perez Garcia  7  8 ,  Gregory A Elder  8  9  10  11 ,  Darren W Engers  1  2  3 ,  Carrie K Jones  1  2  4  3 ,  Craig W Lindsley  1  2  12  4  3
Affiliations
  • 1. Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee 37232, United States.
  • 2. Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States.
  • 3. Vanderbilt Institute for Therapeutic Advances, Vanderbilt University, Nashville, Tennessee 37232, United States.
  • 4. Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, Tennessee 37232, United States.
  • 5. Vanderbilt Brain Institute, Vanderbilt University, Nashville, Tennessee 37240, United States.
  • 6. Vanderbilt Kennedy Center, Vanderbilt University, Nashville, Tennessee 37203, United States.
  • 7. Research and Development Service, James J. Peters Department of Veterans Affairs Medical Center, 130 West Kingsbridge Road, Bronx, New York, New York 10468, United States.
  • 8. Department of Neurology, Icahn School of Medicine at Mount Sinai, One Gustave Levy Place, New York, New York 10029, United States.
  • 9. Department of Psychiatry, Icahn School of Medicine at Mount Sinai, One Gustave Levy Place, New York, New York 10029, United States.
  • 10. Mount Sinai Alzheimer's Disease Research Center and Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, One Gustave Levy Place, New York, New York 10029, United States.
  • 11. Neurology Service, James J. Peters Department of Veterans Affairs Medical Center, 130 West Kingsbridge Road, Bronx, New York, New York 10468, United States.
  • 12. Department of Chemistry, Vanderbilt University, Nashville Tennessee 37232, United States.
PMID: 42334485 DOI: 10.1021/acschemneuro.6c00324
Abstract

Herein, we report the discovery and development of an optimized mGlu2 Negative Allosteric Modulator (NAM) in vivo tool compound, VU6066098, based on a novel, structurally distinct chemotype. VU6066098 is a potent, selective, and CNS-penetrant mGlu2 NAM with excellent rat PK (CLp = 23.9 mL/min/kg, t1/2 = 2.2 h, %F = 100, Kp = 1.28, Kp,uu = 0.25), making it ideal to explore the therapeutic potential of selective mGlu2 inhibition in preclinical rat models. In a rat forced swim test, VU6066098 displayed an oral minimum effective dose (MED) of 1 mg/kg and was equi-efficacious to ketamine. In amphetamine-induced hyperlocomotion, VU6066098 displayed an oral minimum effective dose (MED) of 30 mg/kg. While in the preclinical cognitive tasks of rat novel object recognition and acquisition of contextual fear conditioning, VU6066098 produced robust dose-dependent effects at oral minimum effective doses (MED) of 3 mg/kg and 0.3 mg/kg, respectively. In a blast-related traumatic brain injury (TBI) model, administration of VU6066098 at a dose of 10 mg/kg IP was effective acutely, and the effect on NOR memory was sustained up to 30 days postdose. Thus, mGlu2 NAMs show therapeutic potential for the treatment of a broad range of affective and cognitive symptoms associated with Major Depressive Disorder, Alzheimer's disease, TBI, and acute psychosis; moreover, these data strongly support further optimization of mGlu2 NAMs for future clinical development.

Keywords
amphetamine-induced hyperlocomotion (AHL); blast-related traumatic brain injury (TBI); contextual fear conditioning (CFC); depression; forced swim; metabotropic glutamate receptor subtype 2 (mGlu2); negative allosteric modulator (NAM); novel object recognition (NOR).
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