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Hallucinogen-like effects of 2-([2-(4-cyano-2,5-dimethoxyphenyl) ethylamino]methyl)phenol (25CN-NBOH), a novel N-benzylphenethylamine with 100-fold selectivity for 5-HT2A receptors, in mice

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Abstract

Rationale

2-([2-(4-cyano-2,5-dimethoxyphenyl)ethylamino]methyl)phenol (25CN-NBOH) is structurally similar to N-benzyl substituted phenethylamine hallucinogens currently emerging as drugs of abuse. 25CN-NBOH exhibits dramatic selectivity for 5-HT2A receptors in vitro, but has not been behaviorally characterized.

Objective

25CN-NBOH was compared to the traditional phenethylamine hallucinogen R(-)-2,5-dimethoxy-4-iodoamphetamine (DOI) using mouse models of drug-elicited head twitch behavior and drug discrimination.

Methods

Drug-elicited head twitches were quantified for 10 min following administration of various doses of either DOI or 25CN-NBOH, with and without pretreatments of 0.01 mg/kg 5-HT2A antagonist M100907 or 3.0 mg/kg 5-HT2C antagonist RS102221. The capacity of 25CN-NBOH to attenuate DOI-elicited head twitch was also investigated. Mice were trained to discriminate DOI or M100907 from saline, and 25CN-NBOH was tested for generalization.

Results

25CN-NBOH induced a head twitch response in the mouse that was lower in magnitude than that of DOI, blocked by M100907, but not altered by RS102221. DOI-elicited head twitch was dose-dependently attenuated by 25CN-NBOH pretreatment. 25CN-NBOH produced an intermediate degree of generalization (55 %) for the DOI training dose, and these interoceptive effects were attenuated by M100907. Finally, 25CN-NBOH did not generalize to M100907 at any dose, but ketanserin fully substituted in these animals.

Conclusions

25CN-NBOH was behaviorally active, but less effective than DOI in two mouse models of hallucinogenic effects. The effectiveness with which M100907 antagonized the behavioral actions of 25CN-NBOH strongly suggests that the 5-HT2A receptor is an important site of agonist action for this compound in vivo.

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Acknowledgements

We thank the UAMS Division of Laboratory Animal Medicine for expert husbandry services. This research was generously supported, in part, by an NIGMS IDeA Program award (GM110702), by the UAMS Translational Research Institute (RR029884), and by the Lundbeck Foundation. DS received a Summer Undergraduate Research Fellowship from the American Society of Pharmacology and Experimental Therapeutics which funded his time in the laboratory conducting the head twitch experiments described herein. The views expressed herein are those of the authors and do not necessarily represent the views of the University of Arkansas for Medical Sciences.

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Authors and Affiliations

  1. Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Mail Slot 638, 4301 West Markham Street, Little Rock, AR, 72205, USA

    William E. Fantegrossi

  2. School of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, USA

    Bradley W. Gray

  3. Interdisciplinary Biomedical Sciences Program, University of Arkansas for Medical Sciences, Little Rock, AR, USA

    Jessica M. Bailey

  4. Department of Psychology, Virginia Polytechnic Institute and State University, Blacksburg, VA, USA

    Douglas A. Smith

  5. Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

    Martin Hansen & Jesper L. Kristensen

  6. Center for Integrated Molecular Brain Imaging (CIMBI), Rigshospitalet and University of Copenhagen, Blegdamsvej 9, 2100, Copenhagen, Denmark

    Martin Hansen & Jesper L. Kristensen

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  1. William E. Fantegrossi
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  2. Bradley W. Gray
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  5. Martin Hansen
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Correspondence to William E. Fantegrossi.

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Fantegrossi, W.E., Gray, B.W., Bailey, J.M. et al. Hallucinogen-like effects of 2-([2-(4-cyano-2,5-dimethoxyphenyl) ethylamino]methyl)phenol (25CN-NBOH), a novel N-benzylphenethylamine with 100-fold selectivity for 5-HT2A receptors, in mice. Psychopharmacology 232, 1039–1047 (2015). https://doi.org/10.1007/s00213-014-3739-3

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