VU6001966

VU6001966 is a brain-penetrant and selective mGlu2 receptor inhibitor. VU6001966 blocks mGlu2 receptor activity, counteracts LY379268 (HY-103558)-mediated blood-brain barrier protection and inflammatory cytokine dampening in microglia under inflammatory conditions. VU6001966 enhances antidepressant effects when combined with Scopolamine (HY-N0296). VU6001966 can be used for the research of major depressive disorder^[1][2][3][4]. In Vitro:VU6001966 (3 μM; 24-36 h) does not interfere with the protective effects of LY379268 on TNF-α&IFNγ (T&I)-impaired blood-brain barrier properties, including permeability, TEER, tight junction protein localization in TY-10 human brain microvascular endothelial cell monocultures and permeability, TEER, and claudin-5 expression in TY-10 human brain microvascular endothelial + hAST human astrocyte co-cultures^[1].
VU6001966 (3 μM; 36 h) significantly attenuates the protective effects of LY379268 on T&I-impaired blood-brain barrier permeability and claudin-5 expression in TY-10 human brain microvascular endothelial + hAST human astrocyte + HMC3 human microglial triple co-cultures^[1].
VU6001966 (3 μM; 5 h) significantly reverses the anti-inflammatory effects of LY379268 on T&I-induced cytokine/chemokine expression and blocks the LY379268-induced increase in BDNF expression in HMC3 human microglial cell monocultures^[1].
VU6001966 potently inhibits rmGlu2 in rmGlu2/TREx/Ga15-HEK cells with an IC₅₀ of 78 nM and shows no activity against rmGlu3 in rmGlu3/TREx/Ga15-HEK cells at concentrations up to 30 μM^[4].
VU6001966 does not inhibit CYP3A4, CYP2D6, or CYP2C9 at concentrations up to 30 μM, but inhibits CYP1A2 with an IC₅₀ of 3.1 μM^[4]. In Vivo:VU6001966 (1-10 mg/kg; i.p.; daily; 4 days) treatment dose-dependently alleviates stress-induced anhedonia- and apathy-like behaviors in mice^[2].
VU6001966 (1 mg/kg; i.p.; daily; 4 days) and Scopolamine alleviates UCMS-induced anhedonia- and apathy-like behaviors in mice without affecting non-stressed animals^[2].
Coadministration of VU6001966 (1 mg/kg; i.p.; daily; 4 days) and Scopolamine produces antidepressant-like effects in UCMS-exposed mice that are not blocked by AMPA receptor antagonism, without impairing locomotor activity^[2].
Coadministration of VU6001966 (1 mg/kg; i.p.; daily; 4 days) and Scopolamine produces antidepressant-like effects in UCMS-exposed mice that are dependent on TrkB receptor activation, without impairing locomotor activity^[2].
Coadministration of VU6001966 (1 mg/kg; i.p.; daily; 4 days) and Scopolamine reverses UCMS-induced deficits in TrkB phosphorylation in the mouse prefrontal cortex^[2].
Coadministration of VU6001966 (1 mg/kg; i.p.; daily; 4 days) and Scopolamine does not significantly reverse UCMS-induced impairments in mPFC glutamatergic transmission or synaptic plasticity in mice^[2].
Coadministration of VU6001966 (1 mg/kg; i.p.; daily; 4 days) and Scopolamine does not impair spatial or non-spatial cognitive function in either non-stressed or UCMS-exposed mice^[2].
VU6001966 (1-10 mg/kg; i.p.; single dose) exerts dose-dependent antidepressant-like effects in the rat forced swim test, with the 10 mg/kg dose significantly reducing immobility time without affecting locomotor activity^[3].
VU6001966 (3 mg/kg; i.p.; single dose) significantly enhances antidepressant-like effects in the rat forced swim test, reducing immobility and increasing climbing behavior when coadministered with Scopolamine^[3].
VU6001966 (3 mg/kg; i.p.; single dose) modulates frontal cortex neurotransmitter levels in freely moving rats, increasing serotonin and dopamine while decreasing glutamate, and enhances Scopolamine-induced elevations of these neurotransmitters when coadministered with Scopolamine^[3].