fenobam (AT002) / Autism Therap - LARVOL DELTA

The mGluR5 blockade by MPEP inhibits PKC and triggers AMPK activation reducing hepatic steatosis in vitro (EASL 2025) - " In O/P-treated steatotic HepG2 cells, MPEP, Fenobam, and CPG reduced lipid accumulation dose-dependently... mGluR5 negative allosteric modulators and antagonists reduce fatty acid accumulation in an in vitro steatosis model via selective receptor inhibition. MPEP uniquely modulates both PKC and AMPK, the former with a receptor-independent mechanism."

Preclinical • Hepatology • Metabolic Disorders

Anticancer and Cyclooxygenase Inhibitory Activity of Benzylidene Derivatives of Fenobam and its Thio Analogues. (PubMed, Curr Med Chem) - "Moreover, in silico ADMET predictions showed adequate properties for these compounds, making them promising leads worthy of further optimization."

Journal • Breast Cancer • Cervical Cancer • Oncology • Ovarian Cancer • Solid Tumor

Fenobam modulates distinct electrophysiological mechanisms for regulating excessive gamma oscillations in the striatum of dyskinetic rats. (PubMed, Exp Neurol) - "The temporal characteristics of gamma oscillations provide parameters for classifying LID severity. Antagonizing striatal mGluR5, a promising therapeutic target for dyskinesia, exerts its effects by modulating gamma activity."

Journal • Preclinical • CNS Disorders • Movement Disorders • Parkinson's Disease

The protective effects of methylene blue on astrocytic swelling after cerebral ischemia-reperfusion injuries are mediated by Aquaporin-4 and metabotropic glutamate receptor 5 activation. (PubMed, Heliyon) - "In the cultivated primary ASTs, OGD/R and DHPG significantly increased ASTs volume as well as AQP4 expression, which was reversed by MB and fenobam treatment. The obtained results highlight that MB decreases the post-ischemic brain swelling by regulating the activation of AQP4 and mGluR5, suggesting potential applications of MB on clinical ischemic stroke treatment."

Journal • Cardiovascular • CNS Disorders • Ischemic stroke • Reperfusion Injury • AQP4 • GFAP

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

Group I mGluRs positive allosteric modulators improved schizophrenia-related behavioral and molecular deficits in the Poly I:C rat model. (PubMed, Pharmacol Biochem Behav) - "These results suggest that PAM agents, particularly the mGlu5 receptor VU-29, are also promising and could be a potential target in schizophrenia."

Journal • Preclinical • CNS Disorders • Psychiatry • Schizophrenia

Clinical investigations of compounds targeting metabotropic glutamate receptors. (PubMed, Pharmacol Biochem Behav) - "PET ligands for mGlu5Rs have been studied in a range of patient populations and several mGlu5R antagonists have been tested for potential efficacy in patients including mavoglurant, diploglurant, basimglurant, GET 73, and ADX10059...Fenobam was approved for use as an anxiolytic prior to its recognition as an mGlu5R antagonist. mGlu2/3R agonists (pomaglumated methionil) and mGlu2R agonists (JNJ-40411813, AZD 8529, and LY2979165) have been studied in patients with schizophrenia with promising but mixed results. Antagonists of mGlu2/3Rs (decoglurant and TS-161) have been studied in depression where TS-161 has advanced into a planned Phase 2 study in treatment-resistant depression...The mGlu4R potentiator, foliglurax, did not meet its primary endpoint in patients with Parkinson's disease. Ongoing efforts to develop mGluR-targeted compounds continue to promise these glutamate modulators as medicines for psychiatric and neurological disorders."

Journal • CNS Disorders • Depression • Developmental Disorders • Epilepsy • Fragile X Syndrome • Gastroenterology • Gastroesophageal Reflux Disease • Genetic Disorders • Mental Retardation • Mood Disorders • Movement Disorders • Pain • Parkinson's Disease • Psychiatry • Schizophrenia

DMSO Delays Alzheimer Disease Causing Aβ-induced Paralysis in C. elegans Through Modulation of Glutamate/Acetylcholine Neurotransmission. (PubMed, Ann Neurosci) - "Aldicarb and levamisole assays were performed to identify the contribution of ACh neurotransmission in Αβ toxicity protection by DMSO. Surprisingly, the absence of FOrkhead boXO (FOXO) transcription factor homolog, daf-16 (loss-of-function mutant), a critical transcription factor in the reduced IIS-mediated longevity in C. elegans, abolished DMSO-mediated Ald. DMSO and Fenobam protect against Aβ toxicity through modulation of NT."

Journal • Alzheimer's Disease • CNS Disorders • Dementia • Immunology

Specific changes in sleep oscillations after blocking human metabotropic glutamate receptor 5 in the absence of altered memory function. (PubMed, J Psychopharmacol) - "Notably, under fenobam NonREM spindles became more consistently phase-coupled to the slow oscillation. Our findings indicate that mGluR5-related plasticity is not essential for memory processing during sleep, even though mGlurR5 are strongly implicated in the regulation of the cardinal sleep oscillations."

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Determination of Tautomeric Preference of Fenobam in Solution by High Resolution NMR Spectroscopy. (PubMed, Magn Reson Chem) - "H- H NOESY spectrum revealed that fenobam in liquid state exists exclusively in one of the two possible tautomeric structures, which was confirmed by H- C HSQC and HMBC spectra. Moreover, difference between the two tautomeric structures was studied by theoretical calculations, which further proved the result obtained by the NMR experiments."

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Sleep and Diurnal Rest-Activity Rhythm Disturbances in a Mouse Model of Alzheimer's Disease. (PubMed, Sleep) - "J20 mice have disruptions in rest-activity rhythms and reduced homeostatic sleep pressure (reduced NREM delta power). NREM delta power was increased following treatment with an mGluR5 inhibitor. Drug bioavailability was poor. Further work is necessary to determine if mGluR5 is a viable target for treating sleep phenotypes in AD."

Journal • Preclinical

Expression of metabotropic glutamate 5 receptors in the striatum and cortex and effects of modulators on the severity of dystonia in the phenotypic dt model. (PubMed, Eur J Pharmacol) - "Therefore, we investigated the acute effects of the non-competitive mGlu receptor antagonist fenobam as well as the positive modulator 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB) on the severity of inherited dystonia in the mutant dt hamster, a phenotypic model with age-dependent episodes of dystonia...This difference in mGlu receptor protein may be due to altered protein conformation instead of protein level, as western blots revealed similar amounts of monomeric and dimeric protein in mutant hamsters versus control. Thus, the present data do not provide clear evidence for an important role of the mGlu5 receptor in the pathophysiology and as a therapeutic target for types of inherited dystonia."

Journal

Kinetic and system bias as drivers of metabotropic glutamate receptor 5 allosteric modulator pharmacology. (PubMed, Neuropharmacology) - "The apparent affinity of acetylenic NAMs, MPEP, MTEP and dipraglurant, was dependent on the signaling pathway measured, agonist used, and cell type (HEK293A-rat mGlu-low versus mouse cortical neurons). In contrast, the acetylenic partial NAM, M-5MPEP, and structurally distinct NAMs (VU0366248, VU0366058, fenobam), had similar affinity estimates irrespective of the assay or cellular background. Biased modulation was evident for VU0366248 in mouse cortical neurons where it was a NAM for DHPG-mediated iCa mobilization, but neutral with DHPG in IP accumulation assays. Overall, this study highlights the inherent complexity in mGlu NAM pharmacology that we hypothesize may influence interpretation when translating into preclinical models and beyond in the design and development of novel therapeutics for neuropsychiatric and neurological disorders."

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The pro-psychotic metabotropic glutamate receptor compounds fenobam and AZD9272 share binding sites with monoamine oxidase-B inhibitors in humans. (PubMed, Neuropharmacology) - "The findings are consistent with the hypothesis that both fenobam and AZD9272 bind to the MAO-B, which may be of relevance for understanding the mechanism of the psychosis-like adverse events reported for these compounds. Such understanding may serve as a lead to generate new models for the pathophysiology of psychosis."

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The metabotropic glutamate receptor 5 negative allosteric modulator fenobam: pharmacokinetics, side effects, and analgesic effects in healthy human subjects. (PubMed, Pain) - "Our results suggest highly variable fenobam disposition, and minimal analgesic effects at the dose tested. We suggest that future studies testing analgesic effects of mGlu5 blockade are warranted, but such studies should employ molecules with improved pharmacokinetic profiles."

Adverse events • Clinical • Journal • PK/PD data

Pharmacological Trials with Language Intervention in Fragile X Syndrome (GC-IDD 2019) - "Human early phase trials of mGluR5 NAMs fenobam (Neuropharm), AFQ056 (Novartis) and RO4917523 (Roche) have suggested possible benefit in FXS, but larger phase IIb studies of AFQ056 and RO4917523 failed to meet primary behavioral outcomes in adolescents and adults. To date 12 sites have been trained and opened, including 20 SLPs brought to fidelity on delivery of the PILI intervention and 20 SLPs or psychologists brought to fidelity on the WCS assessment. Ten have been approved for ERP, with consistent ERP output from the same phantom used for standardization across all sites. All 12 sites have completed eye tracker timing and fidelity assessments."

Striatal Inhibition of MeCP2 or TSC1 Produces Sociability Deficits and Repetitive Behaviors. (PubMed, Exp Neurobiol) - "Next, we demonstrated that behavioral changes induced by striatal inhibition of MeCP2 and TSC1 were rescued by D-cycloserine (an NMDA agonist), fenobam (an mGluR5 antagonist), SCH23390 (a D1 antagonist), and/or ecopipam (a D1 partial antagonist), pharmacological drugs that are known to regulate ASD-like symptoms in animal models. Collectively, these results suggest that the dorsal striatum is a critical brain region that, when dysfunctional, produces the core symptoms of ASD."

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