- |||||||||| 2R,6R-hydroxynorketamine hydrochloride ((2R,6R)-HNK) / National Institute of Mental Health, methionine enkephalin (STAT-401) / Immune Therap, Statera BioPharma, Envelta (enkephalin intranasal) / Virpax Pharma
Journal: Ketamine and major ketamine metabolites function as allosteric modulators of opioid receptors. (Pubmed Central) - Oct 17, 2024
opioid receptors; this metabolite is known to have analgesic and antidepressant activity but does not bind to glutamate receptors...Significance Statement We found that ketamine and its major biologically-active metabolites function as potent allosteric modulators of mu, delta, and kappa opioid receptors, with submicromolar concentrations of these compounds synergizing with endogenous opioid peptides such as enkephalin and dynorphin. This allosteric activity may contribute to ketamine's therapeutic effectiveness for treating acute and chronic pain and as a fast-acting antidepressant drug.
- |||||||||| 2R,6R-hydroxynorketamine hydrochloride ((2R,6R)-HNK) / National Institute of Mental Health
Reduction in ethanol consumption in mice following (2R,6R)-Hydroxynorketamine (MCP Hall A) - Aug 22, 2024 - Abstract #Neuroscience2024Neuroscience_7448;
There was an overall treatment effect of (2R,6R)-HNK, reducing ethanol consumption by approximately 10% in both male and female mice, during the treatment week and the week following treatment cessation, indicative of sustained action of the drug. In conclusion, (2R,6R)-HNK may be a novel therapeutic for AUD.
- |||||||||| 2R,6R-hydroxynorketamine hydrochloride ((2R,6R)-HNK) / National Institute of Mental Health
Journal: Ketamine metabolism via hepatic CYP450 isoforms contributes to its sustained antidepressant actions. (Pubmed Central) - Aug 15, 2024
A single (2R,6R)-HNK administration resulted in prevention of the effects of fluconazole on the antidepressant-like activity of ketamine in mice. Overall, these findings are consistent with an essential contribution of (6)-HNK to the sustained antidepressant-like effects of ketamine and suggest potential interactions between pharmacological CYPIs and ketamine during antidepressant treatment in patients.
- |||||||||| 2R,6R-hydroxynorketamine hydrochloride ((2R,6R)-HNK) / National Institute of Mental Health
Effect Of (2r,6r)-Hydroxynorketamine On C-Fos Expression In A Murine Model Of Back Pain (Exhibit Hall) - Jun 25, 2024 - Abstract #ASA2024ASA_1494;
In the current study we observed upregulation of the expression of c-fos in the spinal cord of DP mice compared with (2R,6R)-HNK or sham controls. It has been shown that c-fos, through its protein form, FOS, leads to expression of dynorphin gene and subsequently dynorphin protein.
- |||||||||| morphine sulphate / Generic mfg., 2R,6R-hydroxynorketamine hydrochloride ((2R,6R)-HNK) / National Institute of Mental Health
Preclinical, Journal: Effects of (2R,6R)-hydroxynorketamine in assays of acute pain-stimulated and pain-depressed behaviors in mice. (Pubmed Central) - Apr 23, 2024
Intermittent administration of (2R,6R)-HNK also did not produce antinociceptive effects in the hot plate or pain-depressed locomotor activity assays. These results suggest that (2R,6R)-HNK is unlikely to have efficacy in treating acute pain; however, the efficacy of (2R,6R)-HNK in chronic pain states should continue to be evaluated.
- |||||||||| Spravato (esketamine intranasal) / J&J, 2R,6R-hydroxynorketamine hydrochloride ((2R,6R)-HNK) / National Institute of Mental Health
The Development of Ketamine for Depression: A Long and Winding Road from Inception to Implementation (JW Grand Ballroom 5/6) - Apr 14, 2024 - Abstract #SOBP2024SOBP_607;
These results suggest that (2R,6R)-HNK is unlikely to have efficacy in treating acute pain; however, the efficacy of (2R,6R)-HNK in chronic pain states should continue to be evaluated. Intranasally-administered esketamine (ketamine
- |||||||||| 2R,6R-hydroxynorketamine hydrochloride ((2R,6R)-HNK) / National Institute of Mental Health
Journal: Green Analytical Toxicology procedure for determination of ketamine, its metabolites and analogues in oral fluid samples using dispersive liquid-liquid microextraction (DLLME). (Pubmed Central) - Mar 19, 2024
Ketamine is one of the oldest NPS, with therapeutic use in human and veterinary medicine authorized in several countries, being metabolized mainly into norketamine and 6-hydroxy-norketamine...No matrix interference and good selectivity in the evaluation of 10 different sources of oral fluid and 42 drugs at 500?ng/mL, respectively, were observed. The method was applied in the analysis of 29 authentic oral fluid samples and had its green characteristic evaluated by three different tools: the Green Analytical Procedure Index (GAPI), the Analytical Eco-Scale and the Analytical GREEnness (AGREE) metrics.
- |||||||||| 2R,6R-hydroxynorketamine hydrochloride ((2R,6R)-HNK) / National Institute of Mental Health
Preclinical, Journal: Loss of the sustained antidepressant-like effect of (2R,6R)-hydroxynorketamine in NMDA receptor GluN2D subunit knockout mice. (Pubmed Central) - Feb 28, 2024
When expression levels of GluN2A and GluN2B subunits were evaluated, a decrease in GluN2B protein expression in the nucleus accumbens was found in stressed wildtype mice but not in stressed GluN2D-knockout mice. These results suggest that the GluN2D subunit and possibly the GluN2B subunit are involved in the sustained antidepressant-like effect of (2R,6R)-HNK.
- |||||||||| 2R,6R-hydroxynorketamine hydrochloride ((2R,6R)-HNK) / National Institute of Mental Health
Journal: cAMP-dependent protein kinase signaling is required for (2R,6R)-hydroxynorketamine to potentiate hippocampal glutamatergic transmission. (Pubmed Central) - Jan 9, 2024
We found that the cAMP-PKA-dependent potentiation was not dependent on TrkB activation by BDNF, which functionally delimits the acute synaptic effects of (2R,6R)-HNK from its sustained BDNF-dependent actions in vivo. These results suggest that, by potentiating glutamate release via cAMP-PKA signaling, (2R,6R)-HNK initiates acute adaptations in fast excitatory synaptic transmission that promote structural plasticity leading to maintained antidepressant action.
- |||||||||| 2R,6R-hydroxynorketamine hydrochloride ((2R,6R)-HNK) / National Institute of Mental Health
Trial completion: Phase 1 Evaluation of (2R,6R)-Hydroxynorketamine (clinicaltrials.gov) - Dec 19, 2023
P1, N=74, Completed,
These results suggest that, by potentiating glutamate release via cAMP-PKA signaling, (2R,6R)-HNK initiates acute adaptations in fast excitatory synaptic transmission that promote structural plasticity leading to maintained antidepressant action. Active, not recruiting --> Completed
- |||||||||| 2R,6R-hydroxynorketamine hydrochloride ((2R,6R)-HNK) / National Institute of Mental Health
Journal: The effects of (2R,6R)-hydroxynorketamine on oxycodone withdrawal and reinstatement. (Pubmed Central) - Dec 18, 2023
Finally, we found (2R,6R)-HNK (30mg/kg, sc) had no effect on locomotor activity and thigmotaxis. Together, these results indicate that acute (2R,6R)-HNK has efficacy in some preclinical models of OUD without producing locomotor or anxiety-like side effects.
- |||||||||| 2R,6R-hydroxynorketamine hydrochloride ((2R,6R)-HNK) / National Institute of Mental Health
Reversal of thermal and mechanical hypersensitivity in rat models of inflammatory and peripheral neuropathy pain by (2R,6R)-Hydroxynorketamine (WCC Halls A-C) - Nov 3, 2023 - Abstract #Neuroscience2023NEUROSCIENCE_6232;
Supported By CDMRP Grant W81XWH-21-2-0011(2R,6R)-hydroxynorketamine ((2R,6R)-HNK), has antinociceptive and analgesic effects in several murine models of pain...DISCLAIMER: The opinions or assertions contained herein are the private views of the authors and are not necessarily those of the Uniformed Services University of the Health Sciences or the Department of Defense, USA. RESEARCH SUPPORT: CDMRP - W81XWH-21-2-0011
- |||||||||| 2R,6R-hydroxynorketamine hydrochloride ((2R,6R)-HNK) / National Institute of Mental Health
Effects of ketamine enantiomers and their HNK metabolites on hippocampal synaptic transmission and plasticity (Montreal Bonaventure Hotel (CAN meeting headquarters)) - Jun 10, 2023 - Abstract #CANACN2023CAN_ACN_122;
Conversely, the ketamine metabolites (2S,6S)- and (2R,6R)-HNK had only minor effects on NMDAR transmission and plasticity and, in contrast to previous reports, did not modulate basal AMPAR transmission or paired-pulse facilitation. Together, our findings suggest that a long-lasting modulation of synaptic NMDAR function may contribute to ketamine's sustained actions, independently of its metabolism to HNK.
- |||||||||| 2R,6R-hydroxynorketamine hydrochloride ((2R,6R)-HNK) / National Institute of Mental Health
Enrollment closed, Trial completion date: Phase 1 Evaluation of (2R,6R)-Hydroxynorketamine (clinicaltrials.gov) - May 15, 2023
P1, N=74, Active, not recruiting,
(2R,6R)-HNK may ameliorate negative mood and social avoidance symptoms in PTSD rats by regulating BDNF/mTOR-mediated synaptic structural plasticity in the NAc, providing new targets for the development of anti-PTSD drugs. Recruiting --> Active, not recruiting | Trial completion date: Oct 2023 --> May 2023
- |||||||||| 2R,6R-hydroxynorketamine hydrochloride ((2R,6R)-HNK) / National Institute of Mental Health
Journal: Chronic exposure to (2 (Pubmed Central) - May 2, 2023
Recruiting --> Active, not recruiting | Trial completion date: Oct 2023 --> May 2023 Overall, our findings indicate that (2
- |||||||||| 2R,6R-hydroxynorketamine hydrochloride ((2R,6R)-HNK) / National Institute of Mental Health
Trial completion date, Trial primary completion date: Phase 1 Evaluation of (2R,6R)-Hydroxynorketamine (clinicaltrials.gov) - Feb 8, 2023
P1, N=80, Recruiting,
Overall, our findings indicate that (2 Trial completion date: Apr 2023 --> Oct 2023 | Trial primary completion date: Dec 2022 --> Mar 2023
- |||||||||| 2R,6R-hydroxynorketamine hydrochloride ((2R,6R)-HNK) / National Institute of Mental Health
Journal: (2R,6R)-hydroxynorketamine targeting the basolateral amygdala regulates fear memory. (Pubmed Central) - Dec 25, 2022
Taken together, these results indicated that (2R,6R)-HNK could regulate BLA synaptic transmission and plasticity and act through the BLA to modulate fear memory. The results revealed that (2R,6R)-HNK may be a potential drug to treat posttraumatic stress disorder (PTSD) patients.
- |||||||||| 2R,6R-hydroxynorketamine hydrochloride ((2R,6R)-HNK) / National Institute of Mental Health
Journal: (2R,6R)-hydroxynorketamine (HNK) reverses mechanical hypersensitivity in a model of localized inflammatory pain. (Pubmed Central) - Nov 9, 2022
SIGNIFICANCE: The ketamine metabolite (2R,6R)-HNK reversed mechanical hypersensitivity associated with localized inflammation with onset less than one hour and duration greater than 24 hours in an effect comparable to the NSAID carprofen. Reversal of mechanical hypersensitivity by (2R,6R)-HNK is AMPAR-dependent.
- |||||||||| 2R,6R-hydroxynorketamine hydrochloride ((2R,6R)-HNK) / National Institute of Mental Health
Ipsc-derived neurons from treatment-resistant depression patients and healthy controls respond differently to reelin and (2r,6r)-hnk (SDCC Halls B-H) - Oct 10, 2022 - Abstract #Neuroscience2022NEUROSCIENCE_3502;
HC cell lines may be better at mediating homeostasis after treatment as in TRD, the increased protein expression was reversed at 24 hours, suggesting a mechanistic shift between time points. This study is a forward step towards the development of leading-edge antidepressant therapeutics and the use of novel methodologies to improve the translatability of pharmacological research.
- |||||||||| 2R,6R-hydroxynorketamine hydrochloride ((2R,6R)-HNK) / National Institute of Mental Health
Journal: Antinociceptive and Analgesic Effects of (2R,6R)-hydroxynorketamine. (Pubmed Central) - Aug 22, 2022
(2R,6R)-HNK also reversed allodynia in SNI-operated animals within 4 hours of treatment onset, with a duration of effect lasting longer than gabapentin. Taken together, (2R,6R)-HNK demonstrates the potential for development as a non-opioid analgesic drug.
- |||||||||| 2R,6R-hydroxynorketamine hydrochloride ((2R,6R)-HNK) / National Institute of Mental Health
Journal: Target deconvolution studies of (2R,6R)-hydroxynorketamine: an elusive search. (Pubmed Central) - Jul 1, 2022
However, it could still be possible that both ketamine and (2R,6R)-HNK exert antidepressant-like efficacy through a common and previously unidentified mechanism. Given its pharmacological profile, we predict that (2R,6R)-HNK will exhibit a favorable safety profile in clinical trials, and we must wait for clinical studies to determine its antidepressant efficacy.
- |||||||||| 2R,6R-hydroxynorketamine hydrochloride ((2R,6R)-HNK) / National Institute of Mental Health
Review, Journal: (2R,6R)-hydroxynorketamine rapidly potentiates optically-evoked Schaffer collateral synaptic activity. (Pubmed Central) - Jun 15, 2022
These results demonstrate that (2R,6R)-HNK increases the probability of glutamate release at CA1-projecting Schaffer collateral afferents, which may be involved in the antidepressant-relevant behavioral adaptations conferred by (2R,6R)-HNK in vivo. The current study also establishes proof-of-principle that genetically-encoded light-sensitive proteins can be used to investigate the synaptic plasticity induced by novel antidepressant compounds in neuronal subcircuits.
- |||||||||| 2R,6R-hydroxynorketamine hydrochloride ((2R,6R)-HNK) / National Institute of Mental Health
Enrollment change, Trial completion date, Trial primary completion date: Phase 1 Evaluation of (2R,6R)-Hydroxynorketamine (clinicaltrials.gov) - May 2, 2022
P1, N=80, Recruiting,
The current study also establishes proof-of-principle that genetically-encoded light-sensitive proteins can be used to investigate the synaptic plasticity induced by novel antidepressant compounds in neuronal subcircuits. N=48 --> 80 | Trial completion date: Nov 2021 --> Apr 2023 | Trial primary completion date: Nov 2021 --> Dec 2022
- |||||||||| 2R,6R-hydroxynorketamine hydrochloride ((2R,6R)-HNK) / National Institute of Mental Health
Enrollment open: Phase 1 Evaluation of (2R,6R)-Hydroxynorketamine (clinicaltrials.gov) - Feb 2, 2021
P1, N=48, Recruiting,
N=48 --> 80 | Trial completion date: Nov 2021 --> Apr 2023 | Trial primary completion date: Nov 2021 --> Dec 2022 Not yet recruiting --> Recruiting
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