ADX71743 / Addex - LARVOL DELTA

Negative allosteric modulator of the metabotropic glutamate receptor 7 (mGlu7) ADX71743 increases wakefulness, reduces sleep and alters stress-induced changes in the brain neurotransmitter levels. (PubMed, Int J Neuropsychopharmacol) - "These findings support an important role for mGlu7 in regulating sleep and wakefulness. The ADX71743-associated maintenance of higher vHipp 5-HT and GABA levels after stress may contribute to reduced stress- and anxiety-like reactivity produced by mGlu7 inhibition."

Journal • CNS Disorders • Mood Disorders • Psychiatry • Sleep Disorder

Negative allosteric modulation of mGlu7 disrupts fear memory reconsolidation and glutamatergic signaling in rat and human brain tissue. (PubMed, Mol Psychiatry) - "Moreover, in ex vivo experiments, ADX71743 disinhibited glutamate release, as evidenced by increased spontaneous excitatory postsynaptic currents (EPSCs) frequency and enhanced amplitude of electrically and optogenetically evoked EPSCs at thalamus-to-LA synapses. Finally, application of ADX71743 to human brain tissue mirrored the increased frequency of spontaneous EPSCs observed in the rat LA, underscoring translational relevance. Our findings highlight negative allosteric modulation of mGlu7 as a novel therapeutic avenue for addressing anxiety- and fear-related pathologies, bolstered by the congruent effects of ADX71743 on glutamatergic transmission across species."

Journal • Preclinical • CNS Disorders • Mood Disorders • Psychiatry

mGlu7 inhibition modulates glutamatergic synaptic transmission and disrupts fear memory reconsolidation (Neuroscience 2022) - "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."

CNS Disorders • Cognitive Disorders • Mood Disorders • Psychiatry

Differential activity of mGlu allosteric modulators provides evidence for mGlu heterodimers at hippocampal Schaffer Collateral-CA1 synapses. (PubMed, J Biol Chem) - "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."

Journal • CNS Disorders

Genetic reduction or negative modulation of mGlu7 does not impact anxiety and fear learning phenotypes in a mouse model of MECP2 Duplication syndrome. (PubMed, ACS Chem Neurosci) - "To the contrary, we report that mGlu7 is not functionally increased in mice overexpressing MeCP2 and that neither genetic nor pharmacological reduction of mGlu7 activity impacts phenotypes that are anti-parallel to those observed in Rett syndrome model mice. These data expand our understanding of how mGlu7 expression and function is affected by changes in MeCP2 dosage and have important implications for the therapeutic development of mGlu7 modulators."

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