Elsevier

Neuropharmacology

Volume 99, December 2015, Pages 546-553
Neuropharmacology

Receptor interaction profiles of novel N-2-methoxybenzyl (NBOMe) derivatives of 2,5-dimethoxy-substituted phenethylamines (2C drugs)

https://doi.org/10.1016/j.neuropharm.2015.08.034Get rights and content

Highlights

  • We characterized the pharmacology of N-2-methoxybenzyl-phenethylamines (NBOMes) that are novel psychoactive substances.

  • NBOMe substitution increased the binding affinity at 5-HT2A, 5-HT2C, α1, D1–3, and H1 receptors and monoamine transporters.

  • NBOMes were potent 5-HT2A agonists with high 5-HT2A/5-HT1A selectivity and affinity for α1 receptors and TAAR1.

  • The binding profile of NBOMes predicts strong hallucinogenic effects, similar to LSD, but possibly more stimulant properties.

Abstract

Background

N-2-methoxybenzyl-phenethylamines (NBOMe drugs) are newly used psychoactive substances with poorly defined pharmacological properties. The aim of the present study was to characterize the receptor binding profiles of a series of NBOMe drugs compared with their 2,5-dimethoxy-phenethylamine analogs (2C drugs) and lysergic acid diethylamide (LSD) in vitro.

Methods

We investigated the binding affinities of 2C drugs (2C-B, 2C-C, 2C-D, 2C-E, 2C-H, 2C-I, 2C-N, 2C-P, 2C-T-2, 2C-T-4, 2C-T-7, and mescaline), their NBOMe analogs, and LSD at monoamine receptors and determined functional 5-hydroxytryptamine-2A (5-HT2A) and 5-HT2B receptor activation. Binding at and the inhibition of monoamine uptake transporters were also determined. Human cells that were transfected with the respective human receptors or transporters were used (with the exception of trace amine-associated receptor-1 [TAAR1], in which rat/mouse receptors were used).

Results

All of the compounds potently interacted with serotonergic 5-HT2A, 5-HT2B, 5-HT2C receptors and rat TAAR1 (most Ki and EC50: <1 μM). The N-2-methoxybenzyl substitution of 2C drugs increased the binding affinity at serotonergic 5-HT2A, 5-HT2C, adrenergic α1, dopaminergic D1-3, and histaminergic H1 receptors and monoamine transporters but reduced binding to 5-HT1A receptors and TAAR1. As a result, NBOMe drugs were very potent 5-HT2A receptor agonists (EC50: 0.04–0.5 μM) with high 5-HT2A/5-HT1A selectivity and affinity for adrenergic α1 receptors (Ki: 0.3–0.9 μM) and TAAR1 (Ki: 0.06–2.2 μM), similar to LSD, but not dopaminergic D1–3 receptors (most Ki: > 1 μM), unlike LSD.

Conclusion

The binding profile of NBOMe drugs predicts strong hallucinogenic effects, similar to LSD, but possibly more stimulant properties because of α1 receptor interactions.

Introduction

New psychoactive substances are constantly emerging on the illicit drug market and typically sold via the Internet. Of particular interest are N-2-methoxybenzyl-phenethylamines (NBOMe drugs), which are novel and reportedly very potent hallucinogens that have been increasingly used recreationally (Forrester, 2014, Hill et al., 2013, Ninnemann and Stuart, 2013, Rose et al., 2013, Walterscheid et al., 2014, Wood et al., 2015, Zuba, 2012), with additional potential use as radiotracers (Ettrup et al., 2011, Ettrup et al., 2010). Recreationally used NBOMe drugs include 25I-NBOMe, 25C-NBOMe, 25B-NBOMe, and 25D-NBOMe (Armenian and Gerona, 2014, Poklis et al., 2014, Rose et al., 2013), which are derivatives of 2,5-dimethoxy-4-substituted phenethylamines (2C drugs; Dean et al., 2013, Hill and Thomas, 2011, Shulgin and Shulgin, 1991) (see Fig. 1). N-2-methoxybenzyl substitution enhances the potency of 2C drugs at serotonergic 5-hydroxytryptamine-2A (5-HT2A) receptors, resulting in exceptionally potent 5-HT2A receptor agonists (Braden et al., 2006, Heim, 2004, Nichols et al., 2015) with strong hallucinogenic properties in animals and humans (Halberstadt and Geyer, 2014, Srisuma et al., 2015). Pharmacological interactions between NBOMe drugs and 5-HT2 receptors have been well characterized for some compounds of this novel drug family (Blaazer et al., 2008, Braden et al., 2006, Ettrup et al., 2011, Ettrup et al., 2010, Hansen et al., 2014, Nichols et al., 2008). However, systematic characterizations of the effects of a larger series of NBOMe drugs at a wider range of relevant human receptors and comparisons with their 2C parent drugs are lacking. Importantly, NBOMe drugs have been reported to produce psycho- and cardiovascular stimulant effects, in addition to hallucinations. Specifically, sympathomimetic toxicity, including tachycardia, hypertension, mydriasis, agitation, and hyperthermia, is commonly reported in cases of acute NBOMe drug intoxication (Hill et al., 2013, Rose et al., 2013, Srisuma et al., 2015, Stellpflug et al., 2014, Wood et al., 2015). Pharmacologically, compounds of the 2C series, including 2C-C, 2C-E, and 2C-I, inhibit the norepinephrine (NE) and serotonin transporters (NET and SERT, respectively), similar to amphetamines, although with only very low potency (Eshleman et al., 2014, Nagai et al., 2007). These findings raise the question of whether NBOMe drugs may have similar but more potent stimulant-type pharmacological properties, including inhibition of the NET, dopamine (DA) transporter (DAT), and SERT, or interactions with adrenergic α1 receptors that lead to vasoconstriction.

We assessed the in vitro pharmacology of a series of NBOMe drugs compared with their 2C parent drugs. We characterized the binding affinity profiles at monoamine receptors and DAT, NET, and SERT inhibition potencies. We also determined the functional 5-HT2A receptor activation potencies because 5-HT2A receptors mediate hallucinogenic effects (Nichols, 2004). The prototypical serotonergic hallucinogen lysergic acid diethylamide (LSD) was included as a comparator drug (Nichols, 2004, Passie et al., 2008).

Section snippets

Drugs

2C-B, 2C-C, 2C-D, 2C-E, 2C-H, 2C-I, 2C-N, 2C-P, 2C-T-2, 2C-T-4, 2C-T-7, mescaline, 25B-NBOMe, 25C-NBOMe, 25D-NBOMe, 25E-NBOMe, 25H-NBOMe, 25I-NBOMe, 25N-NBOMe, 25P-NBOMe, 25T2-NBOMe, 25T4-NBOMe, 25T7-NBOMe, and mescaline-NBOMe were synthesized by Lipomed (Arlesheim, Switzerland) for this study at no cost. All of the compounds were used as hydrochloride salts. Purity was >98% for all of the substances. [3H]NE and [3H]DA were obtained from Perkin–Elmer (Schwerzenbach, Switzerland), and [3H]5-HT

Interactions with serotonin receptors

Table 1 shows binding to serotonin 5-HT1A, 5-HT2A, and 5-HT2C receptors, activation potency and efficacy at 5-HT2A and 5-HT2B receptors, and 5-HT receptor binding ratios. All of the compounds exhibited high binding affinity for 5-HT2A and 5-HT2C receptors (Ki < 1 μM, with the exception of 2C-H and mescaline). N-2-methoxybenzyl substitution further increased the average binding affinity for both 5-HT2A and 5-HT2C receptors 26- and 14-fold (range: 6–100 and 8–32, respectively), leading to

Discussion

We pharmacologically characterized the in vitro receptor interaction profiles of novel recreationally abused hallucinogenic N-2-methoxybenzyl-substituted phenethylamines compared with their 2C phenethylamine analogs. Both the NBOMe and 2C drugs potently interacted with serotonin 5-HT2A, 5-HT2B, 5-HT2C receptors and TAAR1rat. We also found several consistent and potentially important structure-affinity relationships for the NBOMe drugs, their 2C analogs, and several targets. Specifically, N

Conflicts of interest

M.C.H. is an employee of F. Hoffmann-La Roche.

Authorship contributions

Participated in research design: Rickli, Liechti.

Conducted experiments: Rickli, Luethi, Reinisch, Buchy.

Performed data analysis: Rickli, Hoener, Liechti.

Wrote or contributed to the writing of the manuscript: Rickli, Liechti.

Acknowledgments

This work was supported by the Federal Office of Public Health (no. 13.006497) and Translational Medicine Hub Innovation Fund of F. Hoffmann-LaRoche and the University of Basel. The authors thank Sylvie Chaboz for technical assistance, Lipomed (Arlesheim, Switzerland) for providing the 2C and NBOMe drugs at no cost, and Michael Arends for text editing.

References (58)

  • D.E. Nichols et al.

    High specific activity tritium-labeled N-(2-2-methoxybenzyl)-2,5-dimethoxy-4-iodophenethylamine (INBMeO): a high-affinity 5-HT2A receptor-selective agonist radioligand

    Bioorg. Med. Chem.

    (2008)
  • A. Rickli et al.

    Monoamine transporter and receptor interaction profiles of novel psychoactive substances: para-halogenated amphetamines and pyrovalerone cathinones

    Eur. Neuropsychopharmacol.

    (2015)
  • P. Saez et al.

    α-Adrenergic and 5-HT2-serotonergic effects of some β-phenylethylamines on isolated rat thoracic aorta

    Gen. Pharmacol.

    (1994)
  • L.D. Simmler et al.

    Monoamine transporter and receptor interaction profiles of a new series of designer cathinones

    Neuropharmacology

    (2014)
  • L.D. Simmler et al.

    Pharmacological profiles of aminoindanes, piperazines, and pipradrol derivatives

    Biochem. Pharmacol.

    (2014)
  • M. Tatsumi et al.

    Pharmacological profile of antidepressants and related compounds at human monoamine transporters

    Eur. J. Pharmacol.

    (1997)
  • C. Acuna-Castillo et al.

    Differences in potency and efficacy of a series of phenylisopropylamine/phenylethylamine pairs at 5-HT2A and 5-HT2C receptors

    Br. J. Pharmacol.

    (2002)
  • F.S. Bersani et al.

    25C-NBOMe: preliminary data on pharmacology, psychoactive effects, and toxicity of a new potent and dangerous hallucinogenic drug

    Biomed. Res. Int.

    (2014)
  • A.R. Blaazer et al.

    Structure-activity relationships of phenylalkylamines as agonist ligands for 5-HT2A receptors

    ChemMedChem

    (2008)
  • M.R. Braden et al.

    Molecular interaction of serotonin 5-HT2A receptor residues Phe339(6.51) and Phe340(6.52) with superpotent N-benzyl phenethylamine agonists

    Mol. Pharmacol.

    (2006)
  • B.V. Dean et al.

    2C or not 2C: phenethylamine designer drug review

    J. Med. Toxicol.

    (2013)
  • B. Di Cara et al.

    Genetic deletion of trace amine 1 receptors reveals their role in auto-inhibiting the actions of ecstasy (MDMA)

    J. Neurosci.

    (2011)
  • A.J. Eshleman et al.

    Behavioral and neurochemical pharmacology of six psychoactive substituted phenethylamines: mouse locomotion, rat drug discrimination and in vitro receptor and transporter binding and function

    Psychopharmacol. Berl.

    (2014)
  • A. Ettrup et al.

    Radiosynthesis and in vivo evaluation of a series of substituted 11C-phenethylamines as 5-HT2A agonist PET tracers

    Eur. J. Nucl. Med. Mol. Imaging

    (2011)
  • A. Ettrup et al.

    Radiosynthesis and evaluation of 11C-CIMBI-5 as a 5-HT2A receptor agonist radioligand for PET

    J. Nucl. Med.

    (2010)
  • W.E. Fantegrossi 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

    Psychopharmacol. Berl.

    (2015)
  • M.B. Forrester

    2C series phenethylamine derivative exposures in Texas

    Subst. Abus.

    (2013)
  • M.B. Forrester

    NBOMe designer drug exposures reported to Texas poison centers

    J. Addict. Dis.

    (2014)
  • R.A. Glennon et al.

    Binding of phenylalkylamine derivatives at 5-HT1C and 5-HT2 serotonin receptors: evidence for a lack of selectivity

    J. Med. Chem.

    (1992)
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