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Cited by 58Psychedelics and Drug StudiesNeurotransmitter Receptor Influence on BehaviorForensic Toxicology and Drug Analysis

Comparative neuropharmacology of N-(2-methoxybenzyl)-2,5-dimethoxyphenethylamine (NBOMe) hallucinogens and their 2C counterparts in male rats

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Elmore, Joshua S., Decker, Ann M., Sulima, Agnieszka, Rice, Kenner C., Partilla, John S., Blough, Bruce E., Baumann, Michael H.·2018·Neuropharmacology
DOI 10.1016/j.neuropharm.2018.02.033PMC PMC6119551
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Abstract

2,5-Dimethoxyphenethylamines (2C compounds) are 5-HT 2A/2C receptor agonists that induce hallucinogenic effects. N-methoxybenzylation of 2C compounds markedly increases their affinity for 5-HT 2A receptors, and two such analogs, 2-(4-chloro-2,5-dimethoxyphenyl)-N-[(2-methoxyphenyl)methyl]ethanamine (25C-NBOMe) and 2-(4-iodo-2,5-dimethoxyphenyl)-N-[(2-methoxyphenyl)methyl]ethanamine (25I-NBOMe), have emerged in recreational drug markets. Here, we investigated the neuropharmacology of 25C-NBOMe and 25I-NBOMe in rats, as compared to their 2C analogs and the prototypical 5-HT 2A/2C agonist 1-(4-iodo-2,5-dimethoxyphenyl)propan-2-amine (DOI). Compounds were tested in vitro using 5-HT 2A receptor binding and calcium mobilization assays. For in vivo experiments, 25C-NBOMe (0.01-0.3 mg/kg), 25I-NBOMe (0.01-0.3 mg/kg), 2-(4-chloro-2,5-dimethoxyphenyl)ethanamine (2C-C) (0.1-3.0 mg/kg), 2-(4-iodo-2,5-dimethoxyphenyl)ethanamine (2C-I) (0.1-3.0 mg/kg) and DOI (0.03-1.0 mg/kg) were administered subcutaneously (sc) to male rats, and 5-HT 2A-mediated behaviors were assessed. NBOMes displayed higher affinity for 5-HT 2A receptors than their 2C counterparts but were substantially weaker in functional assays. 25C-NBOMe and 25I-NBOMe were much more potent at inducing wet dog shakes (WDS) and back muscle contractions (BMC) when compared to 2C-C and 2C-I. Pretreatment with the selective 5-HT 2A antagonist (R)-(2,3-dimethoxyphenyl){1-[2-(4-fluorophenyl)ethyl]-4-piperidinyl}methanol (M100907) reversed behaviors produced by all agonists. Interestingly, binding affinities at the 5-HT 2A receptor were significantly correlated with potencies to induce BMC but not WDS. Our findings show that NBOMes are highly potent 5-HT 2A agonists in rats, similar to effects in mice, and consistent with the reported hallucinogenic effects in human users. This article is part of the Special Issue entitled 'Psychedelics: New Doors, Altered Perceptions'.

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  • Relative to 2C compounds and DOI, N-methoxybenzylated compounds had much higher affinity for 5-HT2A receptors labelled with antagonist ligand [3H]-MDL100907 in vitro.

    “Relative to 2,5-dimethoxyphenethylamines (2C compounds) and DOI, the N-methoxybenzylated compounds had much higher affinity for 5-HT2A receptors labelled with the antagonist ligand [3H]-MDL100907 in vitro [83].”

    From Molecular and Functional Imaging Studies of Psychedelic Drug Action in Animals and Humans. (2021) · cites this paper as [83]

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Authors
Elmore, J. S., Decker, A. M., Sulima, A., Rice, K. C., Partilla, J. S., Blough, B. E., & Baumann, M. H.
Affiliations
  • National Institutes of Health (US)
  • RTI International (US)
Corresponding author
Baumann, Michael H.
ORCID
Venue
Neuropharmacology
Publisher
Elsevier BV
Published
2018-11
Volume
142
Pages
240-250
ISSN
0028-3908 (ISSN-L)
DOI
10.1016/j.neuropharm.2018.02.033
PMC
PMC6119551
OpenAlex
W2794166569
Cited by
58
References
2
Citations by year
2026: 2 · 2025: 9 · 2024: 8 · 2023: 5 · 2022: 6 · 2021: 5 · 2020: 15 · 2019: 5 · 2018: 3
FWCI
8.23
Type
journal article
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Neuropharmacology (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
Intramural Research Program (IRP) of the National Institute on Drug Abuse (NIDA), National Institutes of Health (NIH), United States of America (DA00523)
Topics
  • Social Sciences › Psychology › Clinical Psychology › Psychedelics and Drug Studies
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Toxicology › Forensic Toxicology and Drug Analysis
Keywords
NBOMe, 25I-NBOMe, digital object identifiers, 5-HT2A receptor agonists, 5-HT2C receptor agonist, hallucinogens, wet dog shakes, calcium mobilization
MeSH terms
Animals, Benzylamines, Brain, Dimethoxyphenylethylamine, Dose-Response Relationship, Drug, Fluorobenzenes, Hallucinogens, Humans, Male, Motor Activity, Muscle Contraction, Phenethylamines, Piperidines, Random Allocation, Molecular Structure, Rats, Sprague-Dawley, Serotonin Agents, Head Movements, Receptor, Serotonin, 5-HT2A, Receptor, Serotonin, 5-HT2C, HEK293 Cells, Back Muscles

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