KETAMIR-2, a new molecular entity and novel ketamine analog.
Itzchak Angel, Rita Perelroizen, Wendy Deffains, Florian W Adraoui, Eddy Pichinuk, Erez Aminov
Frontiers in Pharmacology 2025 DOI: 10.3389/fphar.2025.1606976 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical study Peer reviewed |
|---|---|
| Population | Mice |
| Interventions | Ketamir-2 ketamine |
| Topics | Ketamine Esketamine |
| Keywords | Anti-depressant Hyperlocomotion Ketamir-2 Neuropathic pain Ketamine analogs Nmda receptor antagonists Antidepressant treatment Drug safety |
| Citations | 2 |
| Key points | Ketamir-2 is a low-affinity, selective PCP-site NMDA antagonist that does not induce hyperlocomotion in mice and shows anti-depressive and anxiolytic effects in behavioral tests, unlike ketamine. |
Abstract
Ketamir-2 is a new molecular entity, and a novel ketamine analog designed to improve oral bioavailability, and offer a superior safety profile compared to existing ketamine treatments. It was found that Ketamir-2 is a low affinity NMDA receptor antagonist, that selectively binds to the PCP site. Its IC50 on this receptor site is ∼100 µM. Ketamine acts as an NMDA receptor antagonist (0.5-1 µM affinity) and influences opioid receptors, monoaminergic systems (such as serotonin and dopamine). The selectivity of Ketamir-2 was evaluated across a broad range of receptors, transporters, and binding sites, but no activity was detected. Ketamir-2 is a lower affinity and selective PCP-site NMDA antagonist, compared with ketamine. Upon oral administration, Ketamir-2 does not induce hyperlocomotion in mice. Thus, it is different from Ketamine, which induces marked hyperlocomotion, a behavior which is thought to mimic the psychomotor agitation and disorganized behavior seen in schizophrenia, often linked to disruptions in brain neurotransmitter systems. Ketamir-2 was also evaluated via several pharmacological tests in mice to evaluate its anti-depressive and anxiolytic effects. These tests included the Open Field test (OFT), Elevated Plus Maze (EPM), and Forced Swimming Test (FST); all of which are commonly employed behavioral assays used to evaluate the efficacy of anxiety and depression medications. While showing significant effects in these tests at variable doses, ketamine, which was used as a positive control, did not differ from vehicle treatment or showed an opposite response to Ketamir in the majority of the tests studied.
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 12
- Efficacy and Safety of Intranasal Esketamine Adjunctive to Oral Antidepressant Therapy in Treatment-Resistant Depression JAMA Psychiatry December 27, 2017
- Ketamine Pharmacology: An Update (Pharmacodynamics and Molecular Aspects, Recent Findings) CNS Neuroscience & Therapeutics April 10, 2013
- Ketamine for chronic pain: risks and benefits British Journal of Clinical Pharmacology February 21, 2013
- Ketamine: NMDA Receptors and Beyond Journal of Neuroscience November 2, 2016
- Mechanisms of Ketamine and its Metabolites as Antidepressants Biochemical Pharmacology December 1, 2021
and 7 more in the library