Discovery of a Novel Orally Active Ketamine Derivative with Dual Analgesic and Antidepressant Activities, Lacking Psychomimetic Effects.
Syed Muzzammil Masaud, Humaira Nadeem, Babar Murtaza, Abida Shamim
ACS Chemical Neuroscience March 5, 2025 DOI: 10.1021/acschemneuro.4c00887 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical study Peer reviewed |
|---|---|
| Population | Mice |
| Intervention | ketamine |
| Topics | Ketamine Esketamine |
| Keywords | Anesthetic Psychomimetic Pain-relief analgesic Pain management Ketamine-derivatives acetamides Ketamine analogues Mental-health antidepressant Mood disorders Depression treatment Drug-development pharmaceutical research |
| Citations | 3 |
| Key points | Derivative k1 shows comparable analgesic and antidepressant effects to ketamine but with negligible psychomimetic activity. |
Abstract
This study investigated the synthesis, characterization, and in silico analysis of novel N-acetamide ketamine derivatives aimed at evaluating their analgesic, anesthetic, and antidepressant properties. The synthesis commenced with the preparation of chloroacetylamide derivatives, which were subsequently reacted with ketamine hydrochloride, yielding 16 derivatives k1 to k16. These compounds were characterized through H1 NMR, C13 NMR, mass spectroscopy (EIMS), and elemental analysis, followed by an assessment of their physicochemical properties. The analgesic efficacy of all of the synthesized derivatives was evaluated using the acetic acid-induced writhing test via intraperitoneal administration. The best-performing molecule was further evaluated for analgesic (acetic acid-induced writhing test, tail suspension test (TST), and hot plate test) and anti-inflammatory (carrageenan-induced paw edema) activities. For antidepressant effects, all derivatives were compared with ketamine in a lipopolysaccharide-induced model of depression in mice through the forced swimming test, open field test (OFT), sucrose preference test (SPT), and TST. It was observed that among all the derivatives, molecule k1 demonstrated comparable analgesic activity to ketamine. Further, compound k1 also exhibited the highest antidepressant potential during the forced swimming test, OFT, SPT, and TST. k1 was further compared with ketamine for their activities intraperitoneally and orally where k1 exhibited comparable antidepressant effects to ketamine. Henceforth, the psychomimetic potential of k1 was evaluated through loss of righting reflex and Y-maze tests. Very interestingly, these tests indicated approximately no psychomimetic activity of k1 compared to ketamine intraperitoneally and orally. Finally, molecular docking studies were conducted targeting the NMDA receptor at the JC09 ketamine binding pocket (PDB ID: 7EU7), where all synthesized derivatives exhibited significant binding affinities relative to ketamine. These findings suggest that the newly synthesized N-acetamide ketamine derivative k1 possesses promising pharmacological profiles, warranting further exploration.
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 7
- R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects Translational Psychiatry September 1, 2015
- Ketamine: 50 Years of Modulating the Mind Frontiers in Human Neuroscience November 29, 2016
- Ketamine and rapid antidepressant action: new treatments and novel synaptic signaling mechanisms Neuropsychopharmacology July 24, 2023
- Exploring the Molecular Targets for the Antidepressant and Antisuicidal Effects of Ketamine Enantiomers by Using Network Pharmacology and Molecular Docking Pharmaceuticals July 17, 2023
- Role of the AMPA receptor in antidepressant effects of ketamine and potential of AMPA receptor potentiators as a novel antidepressant. Neuropharmacology October 1, 2022
and 2 more in the library