Off-target activity of NBOMes and NBOMe analogs at the µ opioid receptor

Deventer, Marie H; Persson, Mattias; Laus, Antonio; Pottie, Eline; Cannaert, Annelies; Tocco, Graziella; Gréen, Henrik; Stove, Christophe

doi:10.1007/s00204-023-03465-9

Cited by 3 publications

(1 citation statement)

References 64 publications

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“…The following protocol was used to prepare the simulated systems. [35][36][37] The MOR and KOR models were built from the crystallographic structures of M. musculus MOR (PDB ID 6DDF) [23] and H. sapiens KOR (PDB ID 6VI4) coupled to their G-proteins. [24] The MOR and KOR were crystallized in the active state with the agonist [D-Ala 2 , N-MePhe 4 , Glyol]-enkephalin (for MOR) or the agonist (3R)-7-hydroxy-N-{(2S)-1-[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethylpiperidin-1-yl]-3-methylbutan-2-yl}-1,2,3,4-tetrahydroisoquinoline-3-carboxamide (for KOR) occupying the binding site.…”

Section: Molecular Docking Methodsmentioning

confidence: 99%

In silico characterization of ligand–receptor interactions for U‐47700, N,N‐didesmethyl‐U‐47700, U‐50488 at mu‐ and kappa‐opioid receptors

Laus

Kumar

Caboni

et al. 2023

Archiv der Pharmazie

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The increasing misuse of novel synthetic opioids (NSOs) represents a serious public health concern. In this regard, U‐47700 (trans‐3,4‐dichloro‐N‐[2‐(dimethylamino)cyclohexyl]‐N‐methylbenzamide) and related “U‐compounds” emerged on recreational drug markets as synthetic substitutes for illicit heroin and constituents of counterfeit pain medications. While the pharmacology of U‐compounds has been investigated using in vitro and in vivo methods, there is still a lack of understanding about the details of ligand–receptor interactions at the molecular level. To this end, we have developed a molecular modeling protocol based on docking and molecular dynamics simulations to assess the nature of ligand–receptor interactions for U‐47700, N,N‐didesmethyl U‐47700, and U‐50488 at the mu‐opioid receptor (MOR) and kappa‐opioid receptor (KOR). The evaluation of ligand–receptor and ligand–receptor‐membrane interaction energies enabled the identification of subtle conformational shifts in the receptors induced by ligand binding. Interestingly, the removal of two key methyl groups from U‐47700, to form N,N‐didesmethyl U‐47700, caused a loss of hydrogen bond contact with tryptophan (Trp)229, which may underlie the lower interaction energy and reduced MOR affinity for the compound. Taken together, our results are consistent with the reported biological findings for U‐compounds and provide a molecular basis for the MOR selectivity of U‐47700 and KOR selectivity of U‐50488.

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Section: Molecular Docking Methodsmentioning

confidence: 99%

In silico characterization of ligand–receptor interactions for U‐47700, N,N‐didesmethyl‐U‐47700, U‐50488 at mu‐ and kappa‐opioid receptors

Laus

Kumar

Caboni

et al. 2023

Archiv der Pharmazie

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Endogenous opiates and behavior: 2023

Bodnar

2024

Peptides

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Des-acyl ghrelin reduces alcohol intake and alcohol-induced reward in rodents

Witley,

Edvardsson,

Aranäs

et al. 2024

Transl Psychiatry

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The mechanisms contributing to alcohol use disorder (AUD) are complex and the orexigenic peptide ghrelin, which enhances alcohol reward, is implied as a crucial modulator. The major proportion of circulating ghrelin is however the non-octanoylated form of ghrelin, des-acyl ghrelin (DAG), whose role in reward processes is unknown. As recent studies show that DAG decreases food intake, we hypothesize that DAG attenuates alcohol-related responses in animal models. Acute and repeated DAG treatment dose-dependently decreased alcohol drinking in male and female rats. In these alcohol-consuming male rats, repeated DAG treatment causes higher levels of dopamine metabolites in the ventral tegmental area, an area central to reward processing. The role of DAG in reward processing is further supported as DAG prevents alcohol-induced locomotor stimulation, reward in the conditioned place preference paradigm, and dopamine release in the nucleus accumbens in male rodents. On the contrary, DAG does not alter the memory of alcohol reward or affect neurotransmission in the hippocampus, an area central to memory. Further, circulating DAG levels are positively correlated with alcohol drinking in female but not male rats. Studies were conducted in attempts to identify tentative targets of DAG, which currently are unknown. Data from these recombinant cell system revealed that DAG does not bind to either of the monoamine transporters, 5HT2A, CB1, or µ-opioid receptors. Collectively, our data show that DAG attenuates alcohol-related responses in rodents, an effect opposite to that of ghrelin, and contributes towards a deeper insight into behaviors regulated by the ghrelinergic signaling pathway.

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Off-target activity of NBOMes and NBOMe analogs at the µ opioid receptor

Cited by 3 publications

References 64 publications

In silico characterization of ligand–receptor interactions for U‐47700, N,N‐didesmethyl‐U‐47700, U‐50488 at mu‐ and kappa‐opioid receptors

In silico characterization of ligand–receptor interactions for U‐47700, N,N‐didesmethyl‐U‐47700, U‐50488 at mu‐ and kappa‐opioid receptors

Endogenous opiates and behavior: 2023

Des-acyl ghrelin reduces alcohol intake and alcohol-induced reward in rodents

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