Target deconvolution studies of (2R,6R)-hydroxynorketamine: an elusive search

Bonaventura, Jordi; Gómez, Juan L.; Carlton, Meghan L.; Lam, Sherry; Sánchez-Soto, Marta; Morris, Patrick J.; Moaddel, Ruin; Kang, Hye Jin; Zanos, Panos; Gould, Todd D.; Thomas, Craig J.; Sibley, David R.; Zarate, Carlos A.; Michaelides, Michael

doi:10.1038/s41380-022-01673-w

Cited by 24 publications

(16 citation statements)

References 78 publications

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“…The finding that several different antidepressants, seemingly belonging to different chemical classes, such as SSRIs, tricyclic antidepressants, monoamine oxidase inhibitors, and also the rapid-acting antidepressants ketamine and R,R-HNK all bind to TrkB was unexpected. A recent finding failed to find interactions between R,R-HNK and TrkB or any other proteins ( Bonaventura et al, 2022 ), however, concentrations of R,R-HNK tested may have been too low to detect binding to TrkB. Furthermore, in spite of promising preclinical findings ( Hess et al, 2022 ) [but also see Shirayama and Hashimoto (2018) ], whether R,R-HNK produces clinical antidepressant effects have been questioned ( Farmer et al, 2020 ) and remain to be determined in clinical trials.…”

Section: Discussionmentioning

confidence: 99%

BDNF receptor TrkB as the mediator of the antidepressant drug action

Casarotto

Umemori²,

Ċastrén³

2022

Front. Mol. Neurosci.

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Brain-derived neurotrophic factor (BDNF) signaling through its receptor TrkB has for a long time been recognized as a critical mediator of the antidepressant drug action, but BDNF signaling has been considered to be activated indirectly through the action of typical and rapid-acting antidepressants through monoamine transporters and glutamate NMDA receptors, respectively. However, recent findings demonstrate that both typical and the fast-acting antidepressants directly bind to TrkB and thereby allosterically potentiate BDNF signaling, suggesting that TrkB is the direct target for antidepressant drugs. Increased TrkB signaling particularly in the parvalbumin-expressing interneurons orchestrates iPlasticity, a state of juvenile-like enhanced plasticity in the adult brain. iPlasticity sensitizes neuronal networks to environmental influences, enabling rewiring of networks miswired by adverse experiences. These findings have dramatically changed the position of TrkB in the antidepressant effects and they propose a new end-to-end model of the antidepressant drug action. This model emphasizes the enabling role of antidepressant treatment and the active participation of the patient in the process of recovery from mood disorders.

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Section: Discussionmentioning

confidence: 99%

BDNF receptor TrkB as the mediator of the antidepressant drug action

Casarotto

Umemori²,

Ċastrén³

2022

Front. Mol. Neurosci.

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“…Zanos et al showed indeed that ( 2R , 6R )-hydroxynorketamine, but not ketamine, acts at the non-NMDA glutamate α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor ( 9 ). Moreover, a recent study from Bonaventura et al ( 18 ) showed that ( 2R,6R )-hydroxynorketamine displays minimal brain uptake and rapid clearance from the brain, without any affinity for opioid receptors or any other known ketamine targets. Evidently, we need to consider the stereoselective effects of ketamine's metabolites.…”

Section: Discussionmentioning

confidence: 99%

S-Ketamine oral thin film—Part 2: Population pharmacodynamics of S-ketamine, S-norketamine and S-hydroxynorketamine

et al. 2022

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Ketamine is a versatile drug used for many indications and is administered via various routes. Here, we report on the pharmacodynamics of sublingual and buccal fast-dissolving oral-thin-films that contain 50 mg of S-ketamine in a population of healthy male and female volunteers. Twenty volunteers received one or two 50 mg S-ketamine oral thin films in a crossover design, placed for 10 min sublingually (n = 15) or buccally (n = 5). The following measurements were made for 6 h following the film placement: antinociception using three distinct pain assay; electrical, pressure, and heat pain, and drug high on an 11-point visual analog scale. Blood samples were obtained for the measurement of plasma S-ketamine, S-norketamine, and S-hydroxynorketamine concentrations. A population pharmacodynamic analysis was performed in NONMEM to construct a pharmacodynamic model of S-ketamine and its metabolites. P-values < 0.01 were considered significant. The sublingual and buccal 50 and 100 mg S-ketamine oral thin films were antinociceptive and produced drug high with effects lasting 2–6 h, although a clear dose-response relationship for antinociception could not be established. The effects were solely related to the parent compound with no contribution from S-norketamine or S-hydroxynorketamine. S-ketamine potency was lower for antinociception (C50 ranging from 1.2 to 1.7 nmol/mL) than for drug high (C50 0.3 nmol/ml). The onset/offset of effect as defined by the blood-effect-site equilibration half-life did not differ among endpoints and ranged from 0 to 5 min. In conclusion, the 50-mg S-ketamine oral thin film was safe and produced long-term antinociception in all three nociceptive assays with side effects inherent to the use of ketamine. The study was registered at the trial register of the Dutch Cochrane Center (www.trialregister.nl) under identifier NL9267 and the European Union Drug Regulating Authorities Clinical Trials (EudraCT) database under number 2020-005185-33.

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“…; https://doi.org/10.1101/2023.02. 21.529454 doi: bioRxiv preprint 3 of 23 transmembrane helix dimers maintained stable, and binding pocket for the novel ADs: IHCH-7086 and (2R,6R)-HNK was localized in the helix crossing point [9,40]. This discovery expands the list of pharmacological targets from GPCRs and ion channel-type receptors to include RTKs [41,42].…”

Section: Introductionmentioning

confidence: 89%

Reconstruction of TrkB complex assemblies and localizing antidepressant targets using Artificial Intelligence

Xia

Xiang

Yao

et al. 2023

Preprint

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Since Major Depressive Disorder (MDD) represents a neurological pathology caused by inter-synaptic messaging errors, membrane receptors, the source of signal cascades, constitute ap-pealing drugs targets. G protein-coupled receptors (GPCRs) and ion channel receptors chelated antidepressants (ADs) high-resolution architectures were reported to realize receptors physical mechanism and design prototype compounds with minimal side effects. Tyrosine kinase recep-tor 2 (TrkB), a receptor that directly modulates synaptic plasticity, has a finite three-dimensional chart due to its high molecular mass and intrinsically disordered regions (IDRs). Leveraging breakthroughs in deep learning, the meticulous architecture of TrkB was projected employing Alphfold 2 (AF2). Furthermore, the Alphafold Multimer algorithm (AF-M) models the coupling of intra- and extra-membrane topologies to chaperones: mBDNF, SHP2, Etc. Conjugating firmly dimeric transmembrane helix with novel compounds like 2R,6R-hydroxynorketamine (2R,6R-HNK) expands scopes of drug screening to encompass all coding sequences throughout ge-nomes. The operational implementation of TrkB kinase-SHP2, PLCγ1, and SHC1 ensembles has paved the path for machine learning in which it can forecast structural transitions in the self-assembly and self-dissociation of molecules during trillions of cellular mechanisms. In silicon, the cornerstone of the alteration will be artificial intelligence (AI), empowering signal networks to operate at the atomic level and picosecond timescales.

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Target deconvolution studies of (2R,6R)-hydroxynorketamine: an elusive search

Cited by 24 publications

References 78 publications

BDNF receptor TrkB as the mediator of the antidepressant drug action

BDNF receptor TrkB as the mediator of the antidepressant drug action

S-Ketamine oral thin film—Part 2: Population pharmacodynamics of S-ketamine, S-norketamine and S-hydroxynorketamine

Reconstruction of TrkB complex assemblies and localizing antidepressant targets using Artificial Intelligence

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