tulrampator (S47445) / Servier, RespireRx - LARVOL DELTA

All Roads Lead to Glutamate: NMDA and AMPA Receptors as Targets for Rapid-Acting Antidepressants. (PubMed, Pharmacol Res) - "Beyond established rapid-acting antidepressants (RAADs), such as (es)ketamine and dextromethorphan/bupropion (AXS-05), we highlight novel therapeutic directions involving esmethadone (REL-1017), nitrous oxide, and positive allosteric modulators (PAMs) of NMDA receptors (e.g. rapastinel, zelquistinel, and apimostinel). Moreover, we discuss forward-looking strategies using AMPA receptor PAMs (e.g. osavampator and tulrampator) and targeting of AMPA receptor-interacting proteins...Together, targeting glutamatergic signalling represents a transformative path for TRD treatment with high efficacy by more directly modulating pathologically affected signalling modules. These developments place glutamatergic agents at the forefront of next-generation AD strategies."

Journal • Review • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

Oligomeric alpha-synuclein causes early synaptic dysfunction of the corticostriatal pathway associated with non-motor symptoms. (PubMed, NPJ Parkinsons Dis) - "Tulrampator also ameliorated the anxiety-related behavioral phenotype, albeit without attenuating motor deficits, demonstrating its efficacy in mitigating early synaptic and emotional deficits induced by OSyn. These findings provide a basis for a novel drug treatment strategy aimed at mitigating or delaying early damage at cortico-striatal terminals induced by OSyn, thereby counteracting the pathophysiological processes underlying the onset of early non-motor symptoms in PD."

Journal • CNS Disorders • Depression • Inflammation • Mood Disorders • Movement Disorders • Parkinson's Disease • Psychiatry • SLC2A1

ANTI-GLUA3 ANTIBODIES IN FRONTOTEMPORAL DEMENTIA (ADPD 2023) - "Moreover, a group of mice was treated with a well -validated AMPA receptors positive allosteric modulator (PAM, CX-1632) as a possible rescue strategy to co unteract the detrimental effects mediated by anti -GluA3 IgG... Our model allowed to identify the specific contribution o f anti -GluA3 autoantibodies to FTD neuropathology and was instrumental to the development of a personalized therapeutic strategy for GluA3+ FTD patients."

Alzheimer's Disease • CNS Disorders • Dementia • Frontotemporal Lobar Degeneration • Immunology

Pharmacotherapy for the treatment of depression in patients with alzheimer's disease: a treatment-resistant depressive disorder. (PubMed, Expert Opin Pharmacother) - "...Areas covered: The following article looks at the selective serotonin reuptake inhibitor sertraline, which is one of the most frequently studied antidepressant medications in randomized controlled trials (RCTs)...It also gives discussion to the phase II RCT on the alternative drug S47445 and the potential effect on cognition of the multimodal antidepressant vortioxetine in older depressed patients. Finally, it discusses the N-methyl-D-aspartate antagonist ketamine...Future studies are required to identify effective and multimodal pharmacological treatments that efficiently treat depression in AD. Genotyping may boost antidepressant treatment success."

Clinical • Journal • Review • Alzheimer's Disease • Biosimilar • Depression

Efficacy and Safety of 3 Doses of S47445 Versus Placebo in Patients With Alzheimer's Disease at Mild to Moderate Stages With Depressive Symptoms (clinicaltrials.gov) - P2; N=500; Active, not recruiting; Sponsor: Institut de Recherches Internationales Servier; Trial primary completion date: Dec 2017 ➔ Jun 2017

Trial primary completion date • Alzheimer's Disease • Biosimilar • CNS Disorders • Depression

EFFECT OF S47445 ON FUNCTIONAL CONNECTIVITY AT REST AND DURING A TASK, AND ON GLUTAMATE CONCENTRATIONS IN ELDERLY SUBJECTS. (CTAD 2016) - "The main finding is that S 47445 5 mg showed a significant positive effect on functional connectivity during the 2-back task as compared to placebo with a stronger correlation between task-positive networks (attention, working memory) and a negative correlation of the DMN with the attention network. A slight yet significant increase of glutamate concentration (2.4%) was observed with S 47445 at both 5 mg and 20 mg versus placebo assessed by MRS. Collectively, these results suggest that S 47445 enhances functional connectivity between brain networks and induces an increase of excitatory neurotransmission in PCC."

Clinical • Alzheimer's Disease • Biosimilar • CNS Disorders • Depression

S 47445 counteracts the behavioral manifestations and hippocampal neuroplasticity changes in bulbectomized mice. (PubMed, Prog Neuropsychopharmacol Biol Psychiatry) - "Following OB surgery, adult C57BL/6J male mice were chronically administered S 47445 (1, 3 and 10 mg/kg/day; i.p.) and fluoxetine (18 mg/kg/day; i.p.), and then behaviorally tested in the open field test. Chronic administration of S 47445 reversed OB-induced changes in BDNF and phopho-mTOR expression in hippocampus but not in prefrontal cortex. The chronic administration of S 47445 induced antidepressant- and anxiolytic-like effects at low-medium doses (1 and 3 mg/kg/day, i.p.) associated with the reversal of OB-induced changes in hippocampal BDNF and mTOR signaling pathways."

Journal • Preclinical

New procognitive enhancers acting at the histamine H3 and AMPA receptors reverse natural forgetting in mice: comparisons with donepezil and memantine in the object recognition task. (PubMed, Behav Pharmacol) - "This study evaluated the procognitive effects of S 38093 (a new inverse agonist of the histaminergic H3 receptor) and S 47445 (a new α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) in 2-3-month-old Swiss mice as compared with donepezil and memantine, two main reference compounds in the treatment of Alzheimer's disease. S 47445 (1.0, 3.0, and 10.0 mg/kg) and S 38093 (0.3, 1.0, and 3.0 mg/kg), both administered postoperatively, 1 h before familiarization and recognition sessions, rescued memory at the long retention interval; their memory-enhancing effects were as powerful as those obtained with donepezil or memantine (1.0 and 3.0 mg/kg for both compounds). Thus, S 38093 and S 47445, detected as positive controls in the object recognition task, are promising compounds for the treatment of amnesic syndromes."

Journal • Preclinical

A new generation of antidepressants: an update on the pharmaceutical pipeline for novel and rapid-acting therapeutics in mood disorders based on glutamate/GABA neurotransmitter systems. (PubMed, Drug Discov Today) - "Here, we review progress in the development of compounds that act on these systems as well as their purported mechanisms of action. We include glutamate-targeting drugs, such as racemic ketamine, esketamine, lanicemine (AZD6765), traxoprodil (CP-101,606), EVT-101, rislenemdaz (CERC-301/MK-0657), AVP-786, AXS-05, rapastinel (formerly GLYX-13), apimostinel (NRX-1074/AGN-241660), AV-101, NRX-101, basimglurant (RO4917523), decoglurant (RG-1578/RO4995819), tulrampator (CX-1632/S-47445), and riluzole; and GABA-targeting agents, such as brexanolone (SAGE-547), ganaxolone, and SAGE-217."

Journal • Review

A 24-week double-blind placebo-controlled study of the efficacy and safety of the AMPA modulator S47445 in patients with mild to moderate Alzheimer's disease and depressive symptoms. (PubMed, Alzheimers Dement (N Y)) - "There were no specific and/or unexpected safety signals observed with any of the S47445 doses. S47445 administered for 24 weeks was safe and well tolerated by patients with mild to moderate AD; the compound did not show significant benefits over placebo on cognition, function, or depressive symptoms."

Clinical • Journal

A NOVEL ALLOSTERIC MODULATOR OF AMPA RECEPTORS AGAINST ALZHEIMER’S DISEASE PATHOLOGY (ADPD 2019) - "Our findings demonstrated that S47445 compound blocks the stress/Aβ-driven memory deficits providing in vivo support for targeting AMPA receptor signaling against AD synaptic pathology."