zelquistinel (GATE-251) / AbbVie, Gate Neurosciences - LARVOL DELTA

Demystifying the Antidepressant Mechanism of Action of Stinels, a Novel Class of Neuroplastogens: Positive Allosteric Modulators of the NMDA Receptor. (PubMed, Pharmaceuticals (Basel)) - "Stinels-rapastinel, apimostinel, and zelquistinel-are also plastogens not only with rapid and long-term antidepressant effects but also with improved safety and tolerability profiles compared to ketamine. In this review, we present the rationale behind targeting NMDARs for treatment-resistant depression and other psychiatric conditions, describe the various mechanisms by which NMDAR activity is regulated by different classes of therapeutics, and present evidence for the stinel mechanism. In contrast with previous descriptions of glycine-like NMDAR partial agonists, we define stinels as positive allosteric modulators of NMDAR activity with a novel regulatory binding site."

Journal • Review • CNS Disorders • Depression • Psychiatry

GATE-251 or Placebo for the Reduction of Symptoms of Major Depressive Disorder (clinicaltrials.gov) - P2 | N=164 | Recruiting | Sponsor: Gate Neurosciences, Inc | Not yet recruiting ➔ Recruiting | Initiation date: Sep 2024 ➔ Feb 2025

Enrollment open • Trial initiation date • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

GATE-251 or Placebo for the Reduction of Symptoms of Major Depressive Disorder (clinicaltrials.gov) - P2 | N=164 | Not yet recruiting | Sponsor: Gate Neurosciences, Inc

New P2 trial • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

Zelquistinel acts at an extracellular binding domain to modulate intracellular calcium inactivation of N-methyl-D-aspartate receptors. (PubMed, Neuropharmacology) - "These data indicate ZEL is a novel positive allosteric modulator that binds extracellularly and acts through a unique long-distance mechanism to reduce NMDAR CDI, eliciting enhancement of NMDAR current. The critical role that NMDARs play in long-term, activity-dependent synaptic plasticity, learning, memory and cognition, suggests dysregulation of CDI may contribute to psychiatric disorders such as depression, schizophrenia and others, and that the stinel class of drugs can restore synaptic plasticity by reducing activity-dependent CDI."

Journal • CNS Disorders • Depression • Mental Retardation • Psychiatry • Schizophrenia

The NMDA receptor modulator zelquistinel durably relieves behavioral deficits in three mouse models of autism spectrum disorder. (PubMed, Neuropharmacology) - "Efficacy in three mouse models with different etiologies supports high translational value. Further, this compound represents an innovative pharmacological tool to investigate plasticity mechanisms underlying behavioral deficits in animal models of ASD."

Journal • Preclinical • Autism Spectrum Disorder • CNS Disorders • Developmental Disorders • Genetic Disorders • Psychiatry

Gate Neurosciences Announces Clinical Collaboration with Beacon Biosignals to Advance Precision EEG Biomarkers in Major Depressive Disorder (Businesswire) - "Gate Neurosciences...announced a strategic collaboration with Beacon Biosignals to further advance the use of electroencephalogram (EEG) biomarkers across the company’s clinical pipeline in neuropsychiatry and cognition....Initially, this collaboration will entail the use of Beacon Biosignals’ FDA-cleared Dreem™ 3S headband device and neurobiomarker platform to conduct exploratory EEG and sleep analyses in depressed patients enrolled in Gate’s upcoming Phase 2 trial of zelquistinel, slated to initiate by mid-2024."

New P2 trial • CNS Disorders • Depression • Major Depressive Disorder

Zelquistinel is an orally bioavailable novel NMDA receptor allosteric modulator that exhibits rapid and sustained antidepressant-like effects. (PubMed, Int J Neuropsychopharmacol) - "Zelquistinel produces rapid and sustained antidepressant effects by positively modulating the NMDARs, thereby enhancing long-term potentiation (LTP) of synaptic transmission."

Journal • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry • GRIN2A

Zelquistinel (GATE-251) is an orally bioavailable novel NMDA receptor modulator that exhibits rapid and sustained antidepressant-like effects (Neuroscience 2021) - "Here we report that zelquistinel (AGN-241751), a novel, positive NMDAR modulator, exhibits high oral bioavailability and dose-proportional exposures in plasma and the central nervous system and produces sustained antidepressant-like effects in rodents by improving synaptic plasticity. Zelquistinel produces rapid and sustained anti-depressant effects by positively modulating the NMDAR and improving synaptic plasticity. Zelquistinel is currently in phase 2 development as a treatment for MDD."

CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry • GRIN2A

Novel Glutamatergic Modulators for the Treatment of Mood Disorders: Current Status. (PubMed, CNS Drugs) - "This manuscript gives a brief overview of the glutamate system and its relevance to rapid antidepressant response and discusses the existing clinical evidence for glutamate receptor-modulating agents, including (1) broad glutamatergic modulators ((R,S)-ketamine, esketamine, (R)-ketamine, (2R,6R)-hydroxynorketamine [HNK], dextromethorphan, Nuedexta [a combination of dextromethorphan and quinidine], deudextromethorphan [AVP-786], axsome [AXS-05], dextromethadone [REL-1017], nitrous oxide, AZD6765, CLE100, AGN-241751); (2) glycine site modulators (D-cycloserine [DCS], NRX-101, rapastinel [GLYX-13], apimostinel [NRX-1074], sarcosine, 4-chlorokynurenine [4-Cl-KYN/AV-101]); (3) subunit (NR2B)-specific N-methyl-D-aspartate (NMDA) receptor antagonists (eliprodil [EVT-101], traxoprodil [CP-101,606], rislenemdaz [MK-0657/CERC-301]); (4) metabotropic glutamate receptor (mGluR) modulators (basimglurant, AZD2066, RG1578, TS-161); and (5) mammalian target of rapamycin complex 1..."

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

Positive modulation of NMDA receptors by AGN-241751 exerts rapid antidepressant-like effects via excitatory neurons. (PubMed, Neuropsychopharmacology) - "Furthermore, cell-type-specific knockdown of GluN2B-containing NMDARs in mPFC demonstrates that GluN2B subunits on excitatory, but not inhibitory, neurons are necessary for antidepressant-like effects of AGN-241751. Together, these results demonstrate antidepressant-like actions of the NMDAR PAM AGN-241751 and identify GluN2B on excitatory neurons of mPFC as initial cellular trigger underlying these behavioral effects."

Journal • CNS Disorders • Depression • Mood Disorders • Psychiatry

AGN-241751 in the Treatment of Major Depressive Disorder (clinicaltrials.gov) - P1/2; N=223; Completed; Sponsor: Naurex, Inc, an affiliate of Allergan plc; Active, not recruiting ➔ Completed

Clinical • Trial completion

AGN-241751 in the Treatment of Major Depressive Disorder (clinicaltrials.gov) - P1/2; N=220; Active, not recruiting; Sponsor: Naurex, Inc, an affiliate of Allergan plc; Recruiting ➔ Active, not recruiting

Clinical • Enrollment closed

AGN-241751 in the Treatment of Major Depressive Disorder (clinicaltrials.gov) - P2; N=251; Completed; Sponsor: Allergan; Active, not recruiting ➔ Completed

Clinical • Trial completion

AGN-241751 in the Treatment of Major Depressive Disorder (clinicaltrials.gov) - P2; N=250; Active, not recruiting; Sponsor: Allergan; Completed ➔ Active, not recruiting

Clinical • Enrollment closed

AGN-241751 in the Treatment of Major Depressive Disorder (clinicaltrials.gov) - P2; N=250; Completed; Sponsor: Allergan; Recruiting ➔ Completed

Clinical • Trial completion

AGN-241751 in the Treatment of Major Depressive Disorder (clinicaltrials.gov) - P1/2; N=220; Recruiting; Sponsor: Naurex, Inc, an affiliate of Allergan plc; Active, not recruiting ➔ Recruiting

Clinical • Enrollment open

AGN-241751 in the Treatment of Major Depressive Disorder (clinicaltrials.gov) - P1/2; N=220; Active, not recruiting; Sponsor: Naurex, Inc, an affiliate of Allergan plc; Phase classification: P1 ➔ P1/2; N=100 ➔ 220; Trial completion date: May 2019 ➔ Oct 2019; Trial primary completion date: May 2019 ➔ Oct 2019

Clinical • Enrollment change • Phase classification • Trial completion date • Trial primary completion date

AGN-241751 in the Treatment of Major Depressive Disorder (clinicaltrials.gov) - P1; N=100; Active, not recruiting; Sponsor: Naurex, Inc, an affiliate of Allergan plc; Recruiting ➔ Active, not recruiting

Clinical • Enrollment closed

AGN-241751, an Orally Bioavailable Positive NMDA Receptor Modulator, Exhibits Rapid and Sustained Antidepressant-Like Effects in Rodents (SOBP 2019) - "Background: Rapastinel, a positive N-methyl-D-aspartate receptor (NMDAR) modulator, produces rapid and sustained antidepressant effects in patients with major depressive disorder (MDD) but is administered intravenously... NMDAR-mediated activity was measured in hNR2A-D subtype-expressing HEK cells ([3H]MK-801 potentiation assays), cultured rat brain cortical neurons (calcium imaging), and rat hippocampal and/or medial prefrontal cortex (mPFC) slices (electrophysiology assays)... AGN‑241751, a novel positive NMDAR modulator, produced rapid and sustained antidepressant-like effects following oral administration. AGN-241751 has progressed through early 1 development safety studies and is currently in phase 2 clinical testing in patients with MDD"

Preclinical