Computational Analysis of the Binding Poses of Nitazene Derivatives at the mu-Opioid Receptor DOI Creative Commons
Joseph Clayton, Lei Shi, Georgios Skiniotis

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 4, 2024

Nitazenes are a class of novel synthetic opioids with exceptionally high potency. Currently, an experimental structure mu-OR-opioid receptor (muOR) in complex nitazene is lacking. Here we used suite computational tools, including consensus docking, conventional molecular dynamics (MD) and metadynamics simulations, to investigate the muOR binding modes nitro-containing meto-, eto-, proto-, buto-, isotonitazenes nitro-less analogs, metodes-, etodes-, protodesnitazenes. Docking generated three modes, whereby nitro-substituted or unsubstituted benzimidazole group extends into SP1 (subpocket 1 between transmembrane helix TM 2 3), SP2 TM1, TM2, TM7) SP3 3 TM5 TM6). Simulations suggest that etonitazene likely also other nitazenes favor SP2-binding mode. Comparison structures BU72, fentanyl, mitragynine pseudoindoxyl (MP) allows us propose putative model for muOR-ligand recognition which ligand can access hydrophobic hydrophilic SP2, mediated by conformational change Gln1242.60. Interestingly, addition water-mediated hydrogen bonds, nitro forms pi-hole interaction conserved Tyr75. Our analysis provides new insights mechanism muOR-opioid recognition, paving way investigations structure-activity relationships nitazenes.

Language: Английский

In vitro structure–activity relationships and forensic case series of emerging 2-benzylbenzimidazole ‘nitazene’ opioids DOI Creative Commons
Liam M. De Vrieze,

Sara E. Walton,

Eline Pottie

et al.

Archives of Toxicology, Journal Year: 2024, Volume and Issue: 98(9), P. 2999 - 3018

Published: June 14, 2024

Abstract 2-Benzylbenzimidazole ‘nitazene’ opioids are presenting a growing threat to public health. Although various nitazenes were previously studied, systematic comparisons of the effects different structural modifications 2-benzylbenzimidazole core structure on μ-opioid receptor (MOR) activity limited. Here, we assessed in vitro structure–activity relationships 9 uncharacterized alongside known analogues. Specifically, focused MOR activation by ‘ring’ substituted analogues (i.e., N -pyrrolidino and -piperidinyl modifications), ‘desnitazene’ (lacking 5-nitro group), -desethyl The results from two assays (β-arrestin 2 recruitment inhibition cAMP accumulation) showed that overall yield highly active drugs. With exception 4′-OH (which metabolites), substitutions generally more favorable for than -piperidine substitutions. Furthermore, removal group benzimidazole ring consistently caused pronounced decrease potency. important activity, resulted slightly lowered potency comparator nitazenes. Intriguingly, isotonitazene was potent isotonitazene. Complementing findings demonstrating high harm potential associated with many these compounds, describe 85 forensic cases North America United Kingdom involving etodesnitazene, etonitazene, isotonitazene, metonitazene, protonitazene. low-to-sub ng/mL blood concentrations observed most underscore drugs’ potencies. Taken together, bridging pharmacology case data, this study may aid increase awareness guide legislative health efforts.

Language: Английский

Citations

8
Fentanyl–Antibody Interaction as a Novel Strategy against Opiates and Opioids Abuse DOI Creative Commons
Giovanni Ribaudo,

Andrea Achille Taccani,

Alessandra Gianoncelli

et al.

Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: April 3, 2025

While naloxone remains the antidote for opioid overdoses, more efficient tools are required to effectively combat this growing crisis. Vaccines and antibodies targeting substances of abuse appear be a novel promising approach tackling fentanyl epidemic. After an initial in-depth rundown on pharmacodynamics involved from structural mechanistic standpoint, brief overview pharmacological approaches used in clinical settings managing overdoses addiction, Perspective will mainly focused these innovative strategies, based development binding sequestering their generation vivo through vaccines. The most examined, production techniques potential applications, analyzing structures mechanisms antibody-substance interactions comparing with receptor processes.

Language: Английский

Citations

0
A Putative Binding Model of Nitazene Derivatives at the μ-Opioid Receptor DOI
Joseph Clayton, Lei Shi, Michael J. Robertson

et al.

Neuropharmacology, Journal Year: 2025, Volume and Issue: unknown, P. 110437 - 110437

Published: April 1, 2025

Language: Английский

Citations

0
Evaluation of enzyme‐linked immunosorbent assay screening kits for the detection of nitazene analogs DOI

Amanda L. Pacana,

Britni Skillman

Journal of Forensic Sciences, Journal Year: 2025, Volume and Issue: unknown

Published: April 15, 2025

Abstract Nitazene analogs are a highly potent class of novel psychoactive substances (NPS) that were first identified in forensic casework the United States 2019. While enzyme‐linked immunosorbent assay (ELISA) remains prevalent screening tool toxicology laboratories, no nitazene‐specific ELISA kits commercially available, supporting use high‐resolution mass spectrometry (HRMS) methods as more adaptable alternative for screening. However, even with growth popularity HRMS techniques, it is important to understand cross‐reactivity substances, such nitazenes, routinely used kits. Cross‐reactivity particularly since can impact reliability results, potentially leading non‐detection or false‐positive identifications presence non‐target analytes. This study tested seven nitazene (4′‐OH nitazene, 5‐methyl etodesnitazene, isotonitazene, metodesnitazene, N‐piperidinyl etonitazene, N‐pyrrolidino and protonitazene) whole blood using 13 commercial from three manufacturers. Various drug/class selected based on reported potential co‐positivity nitazenes (opiates, opioids, fentanyl) by structural similarities (LSD, zolpidem). Across concentrations analytes, none produced signal sufficient positive result, confirming their at these levels does not compromise specificity target findings highlight need laboratories adopt spectral‐based like advocate development effective analog

Language: Английский

Citations

0
Navigating nitazenes: A pharmacological and toxicological overview of new synthetic opioids with a 2-benzylbenzimidazole core DOI
Marthe M. Vandeputte, Christophe P. Stove

Neuropharmacology, Journal Year: 2025, Volume and Issue: unknown, P. 110470 - 110470

Published: April 1, 2025

Language: Английский

Citations

0
Detection of N-desethyl etonitazene in a drug checking sample: chemical analysis and pharmacological characterization of a recent member of the 2-benzylbenzimidazole “nitazene” class DOI Creative Commons
Manuela Carla Monti, Liam M. De Vrieze, Marthe M. Vandeputte

et al.

Journal of Pharmaceutical and Biomedical Analysis, Journal Year: 2024, Volume and Issue: 251, P. 116453 - 116453

Published: Aug. 25, 2024

The emergence of 2-benzylbenzimidazole "nitazene" opioids is stirring up the recreational synthetic opioid market. Many nitazene analogues act as potent agonists at µ‑opioid receptor (MOR), demonstrated in various vitro and vivo studies. Severe intoxication overdose deaths associated with are increasingly being reported. Nitazene classified a public health threat, stressing need for close monitoring new developments on drug This study reports detection N-desethyl etonitazene sample handed by user Swiss checking service August 2023. person bought through an internet source where it was stated to contain isotonitazene. Chemical analyses were conducted characterize sample, i.e. nuclear magnetic resonance (NMR), capillary electrophoresis (CE), high-resolution mass spectrometry (HRMS). additionally investigated using two different MOR activation assays. NMR high-performance liquid chromatography (HPLC) coupled HRMS confirmed presence high purity absence isotonitazene etonitazene. N-Desethyl have been detected before metabolites However, first seen isotonitazene, they now emerging standalone drugs. applied bioassays increased efficacy approximately 6-9-fold higher potency compared fentanyl. showed EC

Language: Английский

Citations

2
Characterization of novel nitazene recreational drugs: Insights into their risk potential from in vitro µ-opioid receptor assays and in vivo behavioral studies in mice DOI Creative Commons
Marthe M. Vandeputte, Grant C. Glatfelter, Donna Walther

et al.

Pharmacological Research, Journal Year: 2024, Volume and Issue: 210, P. 107503 - 107503

Published: Nov. 7, 2024

2-Benzylbenzimidazole derivatives or 'nitazenes' are increasingly present on the recreational drug market. Here, we report synthesis and pharmacological characterization of 15 structurally diverse nitazenes that might be predicted to emerge grow in popularity. This work expands existing knowledge about 2-benzylbenzimidazole structure-activity relationships (SARs), while also helping stakeholders (e.g., forensic toxicologists, clinicians, policymakers) their risk assessment preparedness for potential next generation nitazenes. In vitro µ-opioid receptor (MOR) affinity was determined via competition radioligand (

Language: Английский

Citations

1
Biased signalling in analgesic research and development DOI Creative Commons
Alexandra E. Conibear, Christopher Bailey, Eamonn Kelly

et al.

Current Opinion in Pharmacology, Journal Year: 2024, Volume and Issue: 76, P. 102465 - 102465

Published: June 1, 2024

Ligand bias offers a novel means to improve the therapeutic profile of drugs. With regard G protein-coupled receptors involved in analgesia, it could be advantageous develop such drugs if analgesic effect is mediated by different cellular signalling pathway than adverse effects associated with drug. Whilst this has been explored over number years for μ receptor, remains unclear whether approach significant benefit treatment pain. Nevertheless, development biased ligands at other CNS does offer some promise future. Here we summarise and discuss recent evidence support this.

Language: Английский

Citations

0
Computational Analysis of the Binding Poses of Nitazene Derivatives at the mu-Opioid Receptor DOI Creative Commons
Joseph Clayton, Lei Shi, Georgios Skiniotis

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 4, 2024

Nitazenes are a class of novel synthetic opioids with exceptionally high potency. Currently, an experimental structure mu-OR-opioid receptor (muOR) in complex nitazene is lacking. Here we used suite computational tools, including consensus docking, conventional molecular dynamics (MD) and metadynamics simulations, to investigate the muOR binding modes nitro-containing meto-, eto-, proto-, buto-, isotonitazenes nitro-less analogs, metodes-, etodes-, protodesnitazenes. Docking generated three modes, whereby nitro-substituted or unsubstituted benzimidazole group extends into SP1 (subpocket 1 between transmembrane helix TM 2 3), SP2 TM1, TM2, TM7) SP3 3 TM5 TM6). Simulations suggest that etonitazene likely also other nitazenes favor SP2-binding mode. Comparison structures BU72, fentanyl, mitragynine pseudoindoxyl (MP) allows us propose putative model for muOR-ligand recognition which ligand can access hydrophobic hydrophilic SP2, mediated by conformational change Gln1242.60. Interestingly, addition water-mediated hydrogen bonds, nitro forms pi-hole interaction conserved Tyr75. Our analysis provides new insights mechanism muOR-opioid recognition, paving way investigations structure-activity relationships nitazenes.

Language: Английский

Citations

0