VU0360172 / Center of Excellence for Translational Neuroscience and Therapeutics - LARVOL DELTA

VU0360172 Exerts Anti-inflammatory Effect on Germinal Matrix Hemorrhage in Neonatal Rats via the mGluR5/PI3Kγ/PPARγ Pathway. (PubMed, J Stroke Cerebrovasc Dis) - "VU3060172 has a neuroprotective effect and anti-inflammatory properties on the GMH mouse model. Its anti-inflammatory mechanism may be achieved by activating the mGluR5/PI3Kγ/PPARγ pathway to regulate microglial polarization."

Journal • Preclinical • Cerebral Hemorrhage • CNS Disorders • Hematological Disorders • Inflammation • PIK3CG • PPARG

Inhibiting metabotropic glutamate receptor 5 after stroke restores brain function and connectivity. (PubMed, Brain) - "Using multiple behavioral tests we observed that treatment with negative allosteric modulators (NAMs) of mGluR5 (MTEP, fenobam, and AFQ056) for 12 days, starting 2 or 10 days after stroke, restored lost sensorimotor functions, without diminishing infarct size...Recovery was prevented by activation of mGluR5 with the positive allosteric modulator VU0360172, and accelerated in mGluR5 KO mice compared to wild-type mice...We conclude that neuronal circuitry subserving sensorimotor function after stroke is depressed by a mGluR5-dependent maladaptive plasticity mechanism that can be restored by mGluR5 inhibition. Post-acute stroke treatment with mGluR5 NAMs combined with rehabilitative training may represent a novel post-acute stroke therapy."

Journal • Cardiovascular • CNS Disorders • Depression • Ischemic stroke • Psychiatry

Blunted type-5 metabotropic glutamate receptor-mediated polyphosphoinositide hydrolysis in two mouse models of monogenic autism. (PubMed, Neuropharmacology) - "We have developed a method for in vivo assessment of PI hydrolysis based on systemic injection of lithium chloride followed by treatment with the selective mGlu5 receptor PAM, VU0360172, and measurement of endogenous inositolmonophosphate (InsP) in brain tissue...These changes were associated with a significant increase in cortical and striatal Homer1 levels and striatal mGlu5 receptor and Gαq levels in AS mice, and with a reduction in cortical mGlu5 receptor and hippocampal Gαq levels, and an increase in cortical phospholipase-Cβ and hippocampal Homer1 levels in FXS mice. This is the first evidence that the canonical transduction pathway activated by mGlu5 receptors is down-regulated in brain regions of mice modeling monogenic autism."

Journal • Preclinical • Autism Spectrum Disorder • CNS Disorders • Depression • Fragile X Syndrome • Genetic Disorders • Psychiatry • UBE3A

Role of BDNF and mGluR5 in Modulating Perseverative, Repetitive Behaviors (SOBP 2023) - "Then, we systemically injected VU0360172, a mGluR5 positive allosteric modulator, and used fiber photometry to record dopamine 1 (D1) or dopamine 2 (D2) cell activity in the nucleus accumbens core (NAc) using D1-Cre or D2-Cre mice cross-bred with BDNF+/- mice...Conclusions BDNF haploinsufficiency leads to compensatory increases in NAc mGluR5 levels in males, priming the CSTC circuit to be sensitive to glutamatergic signaling that perpetuates repetitive behaviors. These findings may lead to novel therapeutic molecular targets for these behaviors."

CNS Disorders • Mental Retardation • Psychiatry • BDNF

Oscillatory Deficits in the Sub-Chronic PCP Rat Model for Schizophrenia Are Reversed by mGlu5 Receptor-Positive Allosteric Modulators VU0409551 and VU0360172. (PubMed, Cells) - "This aligns with previous reports that VU0409551 exhibits preferential activation of the phosphatidylinositol-3-kinase (PI3K) signalling pathway over the PKC cascade. Restoration of the excitatory/inhibitory signalling balance and gamma oscillations may therefore underlie the mGluR5 PAM-mediated correction of scPCP-induced cognitive deficits."

Journal • Preclinical • CNS Disorders • Cognitive Disorders • Psychiatry • Schizophrenia

Spinophilin Limits Metabotropic Glutamate Receptor 5 Scaffolding to the Postsynaptic Density and Cell Type Specifically Mediates Excessive Grooming. (PubMed, Biol Psychiatry) - "These results identify spinophilin as a novel striatal signaling hub molecule in MSNs that cell subtype specifically mediates behavioral, functional, and molecular adaptations associated with repetitive motor dysfunction in psychiatric disorders."

Journal • CNS Disorders • Mental Retardation • Psychiatry

Changes in mGlu5 Receptor Signaling Are Associated with Associative Learning and Memory Extinction in Mice. (PubMed, Life (Basel)) - "Memory extinction was associated with a large up-regulation of mGlu5 receptor-mediated PI hydrolysis in the three brain regions and with increases in mGlu5 receptor and phospholipase-Cβ protein levels in the ventral and dorsal hippocampus, respectively. These findings support a role for mGlu5 receptors in mechanisms underlying spatial learning and suggest that mGlu5 receptors are candidate drug targets for disorders in which cognitive functions are impaired or aversive memories are inappropriately retained."

Journal • Preclinical

The comparative effects of mGlu5 receptor positive allosteric modulators VU0409551 and VU0360172 on cognitive deficits and signalling in the sub-chronic PCP rat model for schizophrenia. (PubMed, Neuropharmacology) - "Thus, the beneficial effects of PAMs on scPCP-induced cognitive impairment are accompanied by at least partial reversal of scPCP-induced elevated levels of p-MAPK and p-AKT, whose dysfunction is strongly implicated in schizophrenia pathology. These promising data imply an important role for mGlu5 receptor signalling pathways in improving cognition in the scPCP model and provide support for mGlu5 receptor PAMs as a possible therapeutic intervention for schizophrenia."

Journal • Preclinical • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Psychiatry • Schizophrenia

Pharmacological activation of mGlu5 receptors with the positive allosteric modulator, VU0360172 modulates thalamic GABAergic transmission. (PubMed, Neuropharmacology) - "In the somatosensory cortex, VU0360172 reduced GABA uptake but did not cause significant changes in GAT-1 protein levels. These findings reveal a novel mechanism of regulation mediated by mGlu5 receptors, which could underlie the powerful anti-absence effect of mGlu5 receptor enhancers in animal models."

Journal • CNS Disorders • Epilepsy

mGlu positive allosteric modulators differentially induce or potentiate desensitization of mGlu signalling in recombinant cells and neurons. (PubMed, J Neurochem) - "Moreover, differential apparent affinities, efficacies and cooperativities with DHPG were observed for VU0360172, VU0409551 and VU0424465 when comparing receptor activation and desensitization in a cell type dependent manner. These data indicate that biased mGlu allosteric modulator pharmacology extends to receptor regulatory processes in a tissue dependent manner, adding yet another layer of complexity to rational mGlu drug discovery."

Journal

Evaluation of metabotropic glutamate receptor 5 allosteric ligands in recombinant and native tissues: evidence for biased agonism and modulation. (Neuroscience 2016) - "Further, VU0360172 exhibited different degrees of cooperativity with DHPG in a signalling pathway-dependent manner. Br J Pharmacol 172(4): 1020-1033. (2) Walker K et al (2001). Neuropharmacology 40(1): 10-19."

Biosimilar • Pain

Modulation of thalamic and cortical GABA transporter: the potential mechanism for the anti-absence activity of mGlu5 receptors. (Neuroscience 2016) - "It has been demonstrated that acute treatment with positive allosteric modulators (PAMs) of mGlu1 and mGlu5 metabotropic glutamate receptors (RO0711401 and VU0360172, respectively) dose dependently reduces the incidence of spike-and wave discharges (SWDs), which are the EEG hallmarks of absence epilepsy, in spontaneously epileptic WAG/Rij rats. Identical findings were obtained in pre-symptomatic WAG/Rij rats (20-24 days of age) and in age-matched non-epileptic Wistar control rats, suggesting that the regulation of GAT-1 by mGlu5 receptors is not restricted to epileptic animals. Our data raise the possibility that activation of mGlu5 receptors controls the incidence of absence seizures by enhancing GABA uptake in the cortico-thalamo-cortical circuitry, thereby restraining the endogenous activation of GABAA and GABAB receptors."

Biosimilar • Epilepsy

In Vivo Non-radioactive Assessment of mGlu5 Receptor-Activated Polyphosphoinositide Hydrolysis in Response to Systemic Administration of a Positive Allosteric Modulator. (PubMed, Front Pharmacol) - "...Using a new ELISA kit we showed that systemic treatment with the selective positive allosteric modulator (PAM) of mGlu5 receptors VU0360172 enhanced InsP formation in different brain regions of CD1 or C57Black mice...In addition, we could demonstrate that endogenous activation of mGlu5 receptors largely accounted for the basal PI hydrolysis particularly in the prefrontal cortex. This method offers opportunity for investigation of mGlu5 receptor signaling in physiology and pathology, and could be used for the functional screening of mGlu5 receptor PAMs in living animals."

Journal • Preclinical • Biosimilar

Enhanced Akt/GSK-3β/CREB signaling mediates the anti-inflammatory actions of mGluR5 positive allosteric modulators in microglia and following traumatic brain injury in male mice. (PubMed, J Neurochem) - "Here we show that the mGluR5 PAM, VU0360172 (VuPAM), regulates microglial inflammatory responses through activation of Akt, resulting in the inhibition of GSK-3β...Taken together, our data show that VuPAM decreases pro-inflammatory microglial activation by modulating Akt/GSK-3β/CREB signaling. These findings serve to clarify the potential neuroprotective mechanisms of mGluR5 PAM treatment after TBI, and suggest novel therapeutic targets for post-traumatic neuroinflammation."

Journal • Preclinical

Postnatal Subconvulsive Activity Selectively Reduces NeuN Antigenicity and Inositol Phosphate Hydrolysis within Certain Limbic Structures of Juvenile Weanling Rats (AES 2019) - "Pups were treated with LiCl (80 mg/kg) followed by the mGlu5 receptor PAM, VU0360172 (10 mg/kg), 1 h prior to sacrifice...We propose that IP3 receptor activity of the mPfcx, thalamus, and amygdala regions is defective in our model of ASD and not rescued by PAMs. Instead, mGluR5 potentiation with PAMs to improve cognition may be a more effective treatment strategy for children with epilepsy."

Preclinical

Activation of mGlu5 metabotropic glutamate receptors protects WaG/Rij rats against spontaneous absence seizures by enhancing GABA re-uptake and restraining tonic inhibition in the thalamus (Neuroscience 2019) - "Similar data were obtained in ex vivo experiments, in which tonic inhibition was largely reduced in thalamic slices of WaG/Rij rats treated systemically with VU0360172. Taken together, these findings demonstrate that activation of mGlu5 receptors enhances GABA clearance and restrain tonic inhibition in the thalamus, thereby disclosing a novel potential strategy for the treatment of absence epilepsy."

Preclinical

Postnatal subconvulsive activity selectively reduces NeuN antigenicity and polyphosphoinositide hydrolysis within limbic structures of juvenile rats (Neuroscience 2019) - "...Pups were treated with LiCl (80 mg/kg) ± the mGlu5 receptor PAM, VU0360172 (10 mg/kg), 1 h prior to sacrifice...We propose that PI hydrolysis is defective in the medial prefrontal cortex, thalamus, and amygdala regions in our model of ASD and is not rescued by pharmacological activation of mGlu5 receptors. Instead, mGlu5 potentiation with PAMs to improve cognition may be a more effective treatment strategy for children with epilepsy."

Preclinical

Identification of monellin as the first naturally-derived proteinaceous allosteric agonist of metabotropic glutamate receptor 5. (PubMed, Basic Clin Pharmacol Toxicol) - "...Furthermore, monellin mGlu agonism was positively modulated by the mGlu pure PAM, VU0360172...Taken together, these data indicate that monellin is an allosteric agonist for mGlu , binding to an allosteric binding site on the N-terminus that is functionally linked to the common class C GPCR allosteric site in a biased manner. This is the first evidence of a naturally-derived proteinaceous allosteric ligand for the mGlu receptor family."

Journal