Ketamine Metabolite (2<i>R</i>,6<i>R</i>)-Hydroxynorketamine Interacts with μ and κ Opioid Receptors

Joseph, Thomas; Bu, Weiming; Lin, Wen-Zhen; Zoubak, Lioudmila; Yeliseev, Alexei; Liu, Renyu; Eckenhoff, Roderic G.; Brannigan, Grace

doi:10.1021/acschemneuro.0c00741

Cited by 18 publications

(5 citation statements)

References 59 publications

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“…For example, the ketamine metabolite (2R,6R)-hydroxynorketamine (HNK) produces antidepressant-relevant effects in the absence of direct inhibition of NMDAR [ 54 , 55 ]. One recent study reported that HNK acts as an inverse agonist of both μ-OR and κ-OR [ 56 ]. Another important molecular pathway implicated in the ketamine’s actions is BDNF/TrkB signaling.…”

Section: Discussionmentioning

confidence: 99%

The endogenous opioid system in the medial prefrontal cortex mediates ketamine’s antidepressant-like actions

Jiang,

DiLeone,

Pittenger

et al. 2024

Transl Psychiatry

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Recent studies have implicated the endogenous opioid system in the antidepressant actions of ketamine, but the underlying mechanisms remain unclear. We used a combination of pharmacological, behavioral, and molecular approaches in rats to test the contribution of the prefrontal endogenous opioid system to the antidepressant-like effects of a single dose of ketamine. Both the behavioral actions of ketamine and their molecular correlates in the medial prefrontal cortex (mPFC) are blocked by acute systemic administration of naltrexone, a competitive opioid receptor antagonist. Naltrexone delivered directly into the mPFC similarly disrupts the behavioral effects of ketamine. Ketamine treatment rapidly increases levels of β-endorphin and the expression of the μ-opioid receptor gene (Oprm1) in the mPFC, and the expression of gene that encodes proopiomelanocortin, the precursor of β-endorphin, in the hypothalamus, in vivo. Finally, neutralization of β-endorphin in the mPFC using a specific antibody prior to ketamine treatment abolishes both behavioral and molecular effects. Together, these findings indicate that presence of β-endorphin and activation of opioid receptors in the mPFC are required for the antidepressant-like actions of ketamine.

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Section: Discussionmentioning

confidence: 99%

The endogenous opioid system in the medial prefrontal cortex mediates ketamine’s antidepressant-like actions

Jiang,

DiLeone,

Pittenger

et al. 2024

Transl Psychiatry

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“…SAFEP relies on flat-well restraint forces applied to DBC, which is defined as the RMSD of ligand coordinates calculated in the reference frame of the receptor’s binding site. Successful application of SAFEP to free energy estimation in membranes has been reported in other studies as well. − …”

Section: Theoretical Framework Of Using Alchemical Free Energy Calcul...mentioning

confidence: 99%

“…However, one should bear in mind that this approach could be computationally demanding due to the larger size of the simulation box required. In another FEP/MD study, the simulation of charged ligands with μ and κ opioid receptors introduced errors in the calculation of the binding free energy that was shown to scale as the inverse of the box length. ,, Since this error arises due to the shifting of the electrostatic potential baseline due to the use of periodic boundary conditions and PME summation, a correction on the binding free energy was applied based on Hummer et al formula . From this formula, the self-term for Ewald summation in a cubic lattice is equal to −2.837297/L, where L is the cube length.…”

Section: Theoretical Framework Of Using Alchemical Free Energy Calcul...mentioning

confidence: 99%

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Alchemical Free Energy Calculations on Membrane-Associated Proteins

Papadourakis,

Sinenka,

Matricon

et al. 2023

J. Chem. Theory Comput.

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Membrane proteins have diverse functions within cells and are well-established drug targets. The advances in membrane protein structural biology have revealed drug and lipid binding sites on membrane proteins, while computational methods such as molecular simulations can resolve the thermodynamic basis of these interactions. Particularly, alchemical free energy calculations have shown promise in the calculation of reliable and reproducible binding free energies of protein–ligand and protein–lipid complexes in membrane-associated systems. In this review, we present an overview of representative alchemical free energy studies on G-protein-coupled receptors, ion channels, transporters as well as protein–lipid interactions, with emphasis on best practices and critical aspects of running these simulations. Additionally, we analyze challenges and successes when running alchemical free energy calculations on membrane-associated proteins. Finally, we highlight the value of alchemical free energy calculations calculations in drug discovery and their applicability in the pharmaceutical industry.

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“…Notably, it has been suggested that the antidepressant effects of ketamine are mechanistically distinct from those leading to the dissociative-hypnotic and rewarding effects that support recreational use and intoxication and may arise from the actions of its biologically active metabolites at distinct pharmacological targets from the parent molecule (Figure ). − Ketamine intoxication in unsupervised settings can lead to overdose, with some cases being fatal . Current treatments for ketamine overdose include largely supportive care measures such as the administration of antibiotics, nonsteroidal anti-inflammatory drugs, steroids, noradrenergic agonists, and anticholinergic agentsthere are no specific antidotes for ketamine intoxication. , …”

Section: Introductionmentioning

confidence: 99%

Family of Structurally Related Bioconjugates Yields Antibodies with Differential Selectivity against Ketamine and 6-Hydroxynorketamine

Zheng

Kyzer

Worob

et al. 2021

ACS Chem. Neurosci.

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The dissociative-hypnotic compound ketamine is being used in an increasingly wide range of therapeutic contexts, including anesthesia, adjunctive analgesia, treatment-resistant depression, but it also continues to be a notable substance of abuse. No specific antidotes exist for ketamine intoxication or overdose. Immunopharmacotherapy has demonstrated the ability to offer overdose protection through production of highly specific antibodies that prevent psychoactive drug penetration across the blood–brain barrier, although antiketamine antibodies have not yet been assessed or optimized for use in this approach. Moreover, generation of specific antibodies also provides an opportunity to address the role of 6-hydroxynorketamine metabolites in ketamine’s rapid-acting antidepressant effect through selective restriction of metabolite access to the central nervous system. Hapten design is a critical element for tuning immune recognition of small molecules, as it affects the presentation of the target antigen and thus the quality and selectivity of the response. Here, we report the synthesis and optimization of carrier protein and conjugation conditions for an initial hapten, norketamine-N-COOH (NK-N-COOH), to optimize vaccination conditions and assess the functional consequences of such vaccination on ketamine-induced behavioral alterations occurring at dissociative-like (50 mg/kg) doses. Iterating from this initial approach, two additional haptens, ketamine-N-COOH (KET-N-COOH) and 6-hydroxynorketamine-N-COOH (HNK-N-COOH), were synthesized to target either ketamine or 6-hydroxynorketamine with greater selectivity. The ability of these haptens to generate antiketamine, antinorketamine, and anti-6-hydroxynorketamine immune responses in mice was then assessed using enzyme-linked immunosorbent assay (ELISA) and competitive surface plasmon resonance (SPR) methods. All three haptens provoked immune responses in vivo, although the KET-N-COOH and 6-HNK-N-COOH haptens yielded antibodies with 5- to 10-fold improvements in affinity for ketamine and/or 6-hydroxynorketamine, as compared to NK-N-COOH. Regarding selectivity, vaccines bearing a KET-N-COOH hapten yielded an antibody response with approximately equivalent K d values against ketamine (86.4 ± 3.2 nM) and 6-hydroxynorketamine (74.1 ± 7.8 nM) and a 90-fold weaker K d against norketamine. Contrastingly, 6-HNK-N-COOH generated the highest affinity and most selective antibody profile, with a 38.3 ± 4.7 nM IC50 against 6-hydroxynorketamine; K d values for ketamine and norketamine were 33- to 105-fold weaker, at 1290 ± 281.5 and 3971 ± 2175 nM, respectively. Overall, these findings support the use of rational hapten design to generate antibodies capable of distinguishing between structurally related, yet mechanistically distinct, compounds arising from the same precursor molecule. As applied to the production of the first-reported anti-6-hydroxynorketamine antibodies to date, this approach demonstrates a promising path forward for identifying the individual and combinatorial roles...

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Ketamine Metabolite (2R,6R)-Hydroxynorketamine Interacts with μ and κ Opioid Receptors

Cited by 18 publications

References 59 publications

The endogenous opioid system in the medial prefrontal cortex mediates ketamine’s antidepressant-like actions

The endogenous opioid system in the medial prefrontal cortex mediates ketamine’s antidepressant-like actions

Alchemical Free Energy Calculations on Membrane-Associated Proteins

Family of Structurally Related Bioconjugates Yields Antibodies with Differential Selectivity against Ketamine and 6-Hydroxynorketamine

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