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  • ||||||||||  ADX88178 / National Institute on Drug Abuse, Addex, foliglurax (PXT2331) / Lundbeck
    Preclinical, Journal:  Metabotropic Glutamate Receptor 4 (mGlu4) Positive Allosteric Modulators Lack Efficacy in Rat and Marmoset Models of L-DOPA-Induced Dyskinesia. (Pubmed Central) -  Mar 11, 2024   
    Given the weak efficacy and side-effect profile of amantadine, alternative strategies to reduce glutamate transmission are being investigated...We hypothesized that two mGlu4 positive allosteric modulators, Lu AF21934 ((1?S,2?R)-N1-(3,4-dichlorophenyl)cyclohexane-1,2-dicarboxamide) and ADX88178 (5-Methyl-N-(4-methylpyrimidin-2-yl)-4-(1H-pyrazol-4-yl)thiazol-2-amine), would provide relief in rat and primate models of L-DOPA-induced dyskinesia...This study found no benefit of mGlu4 positive allosteric modulators in tackling L-DOPA-induced dyskinesia. These findings are concordant with the recent failure of foliglurax in phase II clinical trials supporting the predictive validity of these pre-clinical dyskinesia models, while raising further doubt on the anti-dyskinetic potential of mGlu4 positive allosteric modulators.
  • ||||||||||  raseglurant (ADX-10059) / Addex
    Preclinical, Journal:  Design and validation of a low-cost photomodulator for in vivo photoactivation of a mGluR5 inhibitor. (Pubmed Central) -  Feb 20, 2024   
    They demonstrate the in vivo capabilities of the photomodulator by photoreleasing raseglurant, an mGluR5 inhibitor, to treat pain in an acute rat model and follow this study by showing how to reconfigure the photomodulator to work wirelessly and interface with other biomedical devices. The online version contains supplementary material available at 10.1007/s13534-023-00334-3.
  • ||||||||||  ADX71441 / Indivior
    Sex differences in pathological choice of alcohol over a healthy reward: role of GABAergic transmission in the CeA (WCC Halls A-C) -  Nov 3, 2023 - Abstract #Neuroscience2023NEUROSCIENCE_7956;    
    All together, these results support a higher prevalence to develop addiction-like behaviors in male compared to female rats, which aligns with human epidemiological data. Furthermore, they indicate that decreased expression of GAT-3 within CeA is causal for pathological choice behavior in both sexes and that rescuing impaired GABA clearance due to suppressed GAT-3 expression might be a successful therapeutic mechanism in AUD.
  • ||||||||||  ADX71149 / J&J, Addex
    Trial completion date, Combination therapy:  A Study to Investigate JNJ-40411813 in Combination With Levetiracetam or Brivaracetam in Epilepsy (clinicaltrials.gov) -  Oct 11, 2023   
    P2,  N=160, Recruiting, 
    Furthermore, they indicate that decreased expression of GAT-3 within CeA is causal for pathological choice behavior in both sexes and that rescuing impaired GABA clearance due to suppressed GAT-3 expression might be a successful therapeutic mechanism in AUD. Trial completion date: Apr 2026 --> Apr 2024
  • ||||||||||  ADX106772 / Addex
    Journal:  ADX106772, an mGlu2 receptor positive allosteric modulator, selectively attenuates oxycodone taking and seeking. (Pubmed Central) -  Aug 7, 2023   
    ADX106772 reduced oxycodone self-administration and conditioned reinstatement without affecting SCM self-administration or conditioned reinstatement. ADX106772 reduced oxycodone taking and seeking and did not affect the motivation for the palatable conventional reinforcer, suggesting that activating mGlu2 receptors with a positive allosteric modulator is a potential approach for prescription OUD treatment.
  • ||||||||||  dipraglurant-IR (ADX-48621) / Addex, Daxxify (daxibotulinumtoxinA) / Revance Therap
    Journal:  An overview of the pharmacotherapeutics for dystonia: advances over the past decade. (Pubmed Central) -  Nov 18, 2022   
    The most novel emerging therapies include daxibotulinumtoxinA, dipraglurant, and sodium oxybate. There is a strong clinical need for more effective therapeutic options in dystonia, which may involve the development of individualized treatment options based on dystonia subtype, etiology, or novel mechanisms of action that target specific underlying contributing features.
  • ||||||||||  ADX71743 / Addex
    Journal:  Differential activity of mGlu allosteric modulators provides evidence for mGlu heterodimers at hippocampal Schaffer Collateral-CA1 synapses. (Pubmed Central) -  Nov 3, 2022   
    Group III mGlu agonist-induced suppression of evoked excitatory potentials and induction of long-term potentiation at Schaffer collateral-CA1 (SC-CA1) synapses in the rodent hippocampus can be blocked by the selective mGlu negative allosteric modulator (NAM), ADX71743...Building on this hypothesis, we identified two additional structurally related mGlu NAMs that also differ in their activity at mGlu heterodimers, in a manner consistent with their ability to inhibit synaptic transmission and plasticity at SC-CA1. Thus, we propose that mGlu heterodimers are a key molecular target for modulating the activity of hippocampal SC-CA1 synapses.
  • ||||||||||  ADX71743 / Addex
    mGlu7 inhibition modulates glutamatergic synaptic transmission and disrupts fear memory reconsolidation (SDCC Halls B-H) -  Oct 10, 2022 - Abstract #Neuroscience2022NEUROSCIENCE_7580;    
    Tested in amygdala and cortical neurons of human brain tissue, ADX71743 increased spontaneous EPSC frequency similarly as in rats. Our data indicate that negative allosteric modulation of mGlu7 constitutes a new potential mechanism for the treatment of traumatic fear memories and phobia following fear memory recall, with promising translational value considering the comparable effects of ADX71743 on neuronal transmission in rats and humans.
  • ||||||||||  Journal:  Current and future pharmacotherapy options for drug-resistant epilepsy. (Pubmed Central) -  Sep 30, 2022   
    For specific epilepsy syndromes, XEN 496 is under Phase III development for potassium voltage-gated channel subfamily Q member 2 developmental and epileptic encephalopathy (KCNQ2-DEE), carisbamate is under Phase III development for LGS and Ganaxolone under Phase III development for TSC. Finally, in preclinical models several molecular targets including inhibition of glycolysis, neuroinflammation and sodium channel inhibition have been identified in animal models although further data in animal and later human studies are needed.
  • ||||||||||  Journal:  Clinical investigations of compounds targeting metabotropic glutamate receptors. (Pubmed Central) -  Sep 14, 2022   
    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.
  • ||||||||||  Ztalmy (ganaxolone oral) / Marinus
    P2/3 data, Clinical Trial,Phase III, Journal:  Epilepsy: Expert opinion on emerging drugs in phase 2/3 clinical trials. (Pubmed Central) -  Apr 6, 2022   
    Novel mechanisms of action involve cholesterol degradation, mitochondrial pathways, anti-inflammation and neuro-regeneration. Earlier identification of genetic conditions through genetic testing will allow for earlier use of disease specific and disease-modifying therapies.
  • ||||||||||  ADX88178 / National Institute on Drug Abuse, Addex
    Journal:  New 1,2,4-oxadiazole derivatives with positive mGlu receptor modulation activity and antipsychotic-like properties. (Pubmed Central) -  Feb 24, 2022   
    Five modulators (34, 37, 52, 60 and 62) demonstrated significant anxiolytic- and antipsychotic-like properties in the SIH and DOI-induced head twitch test, respectively. Promising data were obtained, especially for N-(4-(5-(2-chlorophenyl)-1,2,4-oxadiazol-3-yl)-3-methylphenyl)picolinamide (62), whose effects in the DOI-induced head twitch test were comparable to those of clozapine and better than those reported for the selective mGlu PAM ADX88178.
  • ||||||||||  ADX71149 / J&J, Addex
    Enrollment open, Combination therapy:  A Study to Investigate JNJ-40411813 in Combination With Levetiracetam or Brivaracetam in Epilepsy (clinicaltrials.gov) -  May 4, 2021   
    P2,  N=160, Recruiting, 
    Our data indicate for the first time that a consistent, unified relationship can be observed between exposure and mGlu receptor occupancy when unbound brain concentration and receptor affinity are taken into account across a range of species for a diverse set of mGlu NAMs, including a new drug candidate, HTL0014242. Not yet recruiting --> Recruiting
  • ||||||||||  fenobam (AT002) / Autism Therapeutics, dipraglurant-IR (ADX-48621) / Addex
    Journal:  Kinetic and system bias as drivers of metabotropic glutamate receptor 5 allosteric modulator pharmacology. (Pubmed Central) -  Jan 29, 2020   
    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.
  • ||||||||||  mavoglurant (AFQ056) / Novartis, dipraglurant-IR (ADX-48621) / Addex
    Review, Journal:  Pathophysiological clues to therapeutic applications of glutamate mGlu5 receptor antagonists in levodopa-induced dyskinesia. (Pubmed Central) -  Dec 23, 2019   
    Beneficial effects of other mGlu5 antagonists such as AFQ056/mavoglurant and ADX48621/dipraglurant in amelioration of LID has been shown not only in animal models but also in clinical trials. Considering the presence of mGlu receptor dysregulation in rapid eye movement (REM) sleep behavior disorder and depression, which are prodromal signs of PD, along with neuroprotective effects of mGlu receptor antagonists, and their cognitive benefits, potential effectiveness of mGlu receptor antagonists in early prevention of PD remains to be investigated.
  • ||||||||||  ADX71149 / J&J, Addex
    Journal:  mGluR2 positive allosteric modulators: an updated patent review (2013-2018). (Pubmed Central) -  Jul 13, 2019   
    ...Negative phase 2 schizophrenia clinical trials with JNJ-40411813 and AZD8529 seem to have tempered the high expectations of the scientific community on the utility of mGlu2 PAMs for the treatment of schizophrenia...The advances in medicinal chemistry and in pharmacology, with novel indications such as epilepsy, have set the stage in the field of mGlu2 receptor PAMs. Ongoing preclinical and clinical studies will contribute to define their optimal therapeutic indication and potential to become novel therapeutic agents.
  • ||||||||||  Journal:  Glutamatergic Modulators in Depression. (Pubmed Central) -  Jun 7, 2019   
    These results have prompted the repurposing or development of other glutamatergic modulators, both as monotherapy or adjunctive to other therapies. Here, we highlight the evidence supporting the antidepressant effects of various glutamatergic modulators, including (1) broad glutamatergic modulators (ketamine, esketamine, dextromethorphan, dextromethorphan-quinidine [Nuedexta], AVP-786, nitrous oxide [N2O], AZD6765), (2) subunit (NR2B)-specific N-methyl-D-aspartate (NMDA) receptor antagonists (CP-101,606/traxoprodil, MK-0657 [CERC-301]), (3) glycine-site partial agonists (D-cycloserine, GLYX-13, sarcosine, AV-101), and (4) metabotropic glutamate receptor modulators (AZD2066, RO4917523/basimglurant, JNJ40411813/ADX71149, R04995819 [RG1578]).
  • ||||||||||  dizocilpine (MK801) / Merck (MSD), basimglurant (RG7090) / Roche, ADX 47273 / Addex
    Journal:  Bidirectional variation in glutamate efflux in the medial prefrontal cortex induced by selective positive and negative allosteric mGluR5 modulators. (Pubmed Central) -  Apr 28, 2019   
    The effect of MK801 (0.03-0.06 mg/kg, s.c.) on mPFC glutamate efflux was also investigated in addition to the effects of MK801 (0.03 mg/kg, s.c.) following ADX47273 (100 mg/kg, p.o.) pre-treatment...These findings indicate that positive and negative allosteric mGluR5 modulators produce long lasting and opposing actions on extracellular glutamate efflux in the mPFC. Positive and negative allosteric modulators of mGluR5 may therefore be viable therapeutic agents to correct abnormalities in glutamatergic signalling present in a range of neuropsychiatric disorders.
  • ||||||||||  dipraglurant-IR (ADX-48621) / Addex
    Trial completion:  PET Imaging Study to Evaluate the mGlu5r Occupancy Following ADX48621 (Dipraglurant) Administration (clinicaltrials.gov) -  Aug 17, 2018   
    P1,  N=12, Completed, 
    Positive and negative allosteric modulators of mGluR5 may therefore be viable therapeutic agents to correct abnormalities in glutamatergic signalling present in a range of neuropsychiatric disorders. Active, not recruiting --> Completed