Pharmacological characterisation of JNJ-78911118, a novel, centrally-penetrant, selective GluN2A antagonist.
Brian Lord, Sirak Simavorian, Ian Fraser, Natalie Welty, Ryan Wyatt, Rory Pritchard, Lauren Fletcher, Henk Van Der Linde, Dominic Bounkhoun, Ondrej Libiger, Michael Maher, Wayne C. Drevets, François Bischoff, Pascal Bonaventure, Robert A Neff
British Journal of Pharmacology May 13, 2025 DOI: 10.1111/bph.70069 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical study Peer reviewed |
|---|---|
| Population | Rats and mice |
| Intervention | JNJ-78911118 |
| Topics | Ketamine |
| Keywords | Cp‐101,606 Glun2a Jnj‐78911118 Depression treatment Neuroscience research Nmda receptor antagonists Psychopharmacology Antidepressants |
| Citations | 2 |
| Key points | Selective GluN2A antagonism with JNJ-78911118 reproduces the effects of known rapidly acting antidepressants on neurotransmitter levels and synaptic plasticity, without causing Olney's lesions, but with acute cardiovascular effects. |
Abstract
Non-selective NMDA receptor antagonism produces rapid symptom improvement in treatment-resistant depression; however, associated side effects necessitate medical oversight during administration. We hypothesised that selective GluN2A antagonism could provide similar efficacy with an improved side effect profile. Here, we report the pharmacology of JNJ-78911118, a brain-penetrant, GluN2A selective antagonist. JNJ-78911118 pharmacology and mechanism of action was characterised in vitro using fluorescence, voltage clamp and radioligand binding assays. Target engagement was measured using ex vivo receptor autoradiography, and effects on rat prefrontal cortex monoamine levels were measured using microdialysis. Synaptogenesis assays and patch clamp studies were used to demonstrate effects on synaptic plasticity. Cardiovascular safety and neurotoxicity were assessed in rats. JNJ-78911118 blocked GluN1/2A receptors with an IC50 of 44 nM and showed selectivity against GluN1/2B, 2C and 2D receptors. Systemic administration produced concentration-dependent receptor occupancy, increased prefrontal cortex monoamine levels in wild type, but not in GluN2A knockout mice, and blocked theta burst induced LTP in the hippocampus. In addition, it produced increases in dendritic complexity and synapse number in vitro, and increased mEPSC frequency in rat cortical neurons in vivo. In rat toxicological studies, no Olney's lesions were observed, but acute increases in heart rate and blood pressure were detected. JNJ-78911118 is a potent and selective GluN2A antagonist that reproduces the effect of known rapidly acting antidepressants (RAADs) on neurotransmitter levels and synaptic plasticity. This molecule is a powerful in vivo tool that will enhance understanding of GluN2A biology.
Comparable studies
Other preclinical and animal studies on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Rats | 2010 | Observational study | |
| Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex Conscious rats | 1997 | Dose-response study with microdialysis and behavioral testing | |
| NMDAR inhibition-independent antidepressant actions of ketamine metabolites Mice | 2016 | Preclinical study | |
| The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N‐methyl‐aspartate Spinal neurons in decerebrate or pentobarbitone-anaesthetized cats and rats | 1983 | Experimental study | |
| R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects Mice | 2015 | Experimental study |
Citations in the library
Cites 8
- mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Science August 19, 2010
- Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex Journal of Neuroscience April 15, 1997
- Ketamine Safety and Tolerability in Clinical Trials for Treatment-Resistant Depression The Journal of Clinical Psychiatry September 2, 2014
- Neurotrophic mechanisms underlying the rapid and sustained antidepressant actions of ketamine. Pharmacology, Biochemistry, and Behavior December 9, 2019
- Novel Antidepressants in the Pipeline (Phase II and III): A Systematic Review of the US Clinical Trials Registry Pharmacopsychiatry January 19, 2022
and 3 more in the library