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

Authors

Coleman JS Jeremy S , Capstick RA Rory A , Chang S Sichen , Rios DJ Derek J , Bubser M Michael , Thompson Gray AD Analisa D , Zagol-Ikapitte I Irene , Krishnan S Srinivasan , Cho HP Hyekyung P , Rodriguez AL Alice L , Niswender CM Colleen M , Boutaud O Olivier , Garcia GP Georgina Perez , Elder GA Gregory A , Engers DW Darren W , Jones CK Carrie K , Lindsley CW Craig W .
ACS chemical neuroscience. 2026 06 23; ().

Abstract

Herein, we report the discovery and development of an optimized mGlu Negative Allosteric Modulator (NAM) tool compound, VU6066098, based on a novel, structurally distinct chemotype. VU6066098 is a potent, selective, and CNS-penetrant mGlu NAM with excellent rat PK (CL = 23.9 mL/min/kg, = 2.2 h, %F = 100, K = 1.28, K = 0.25), making it ideal to explore the therapeutic potential of selective mGlu 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, mGlu 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 mGlu NAMs for future clinical development.