Neurochemical pharmacology of psychoactive substituted N-benzylphenethylamines: High potency agonists at 5-HT2A receptors

Amy J. Eshleman, Katherine M. Wolfrum, John F. Reed, Sunyoung O. Kim, Robert A. Johnson, Aaron Janowsky

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

The use of new psychoactive substituted 2,5-dimethoxy-N-benzylphenethylamines is associated with abuse and toxicity in the United States and elsewhere and their pharmacology is not well known. This study compares the mechanisms of action of 2-(2,5-dimethoxy-4-methylphenyl)-N-(2-methoxybenzyl)ethanamine (25D-NBOMe), 2-(4-ethyl-2,5-dimethoxyphenyl)-N-(2-methoxybenzyl)ethanamine (25E-NBOMe), 2-(2,5-dimethoxyphenyl)-N-(2-methoxybenzyl)ethanamine (25H-NBOMe), 2-(((4-iodo-2,5-dimethoxyphenethyl)amino)methyl)phenol (25I-NBOH); and 2-(2,5-dimethoxy-4-nitrophenyl)-N-(2-methoxybenzyl)ethanamine) (25N-NBOMe) with hallucinogens and stimulants. Mammalian cells heterologously expressing 5-HT1A, 5-HT2A, 5-HT2B or 5-HT2C receptors, or dopamine, serotonin or norepinephrine transporters (DAT, SERT and NET, respectively) were used to assess drug affinities at radioligand binding sites. Potencies and efficacies were determined using [35S]GTPγS binding assays (5-HT1A), inositol-phosphate accumulation assays (5-HT2A 5-HT2B and 5-HT2C), and uptake and release assays (transporters). The substituted phenethylamines were very low potency and low efficacy agonists at the 5-HT1A receptor. 25D-NBOMe, 25E-NBOMe, 25H-NBOMe, 25I-NBOH and 25N-NBOMe had very high affinity for, and full efficacy at, 5-HT2A and 5-HT2C receptors. In the 5-HT2A receptor functional assay, 25D-NBOMe, 25E-NBOMe, 25I-NBOH and 25N-NBOMe had subnanomolar to low nanomolar potencies similar to (+)lysergic acid diethylamide (LSD) while 25H-NBOMe had lower potency, similar to serotonin. At the 5-HT2C receptor, four had very high potencies, similar to LSD and serotonin, while 25H-NBOMe had lower potency. At the 5-HT2B receptor, the compounds had lower affinity, potency and efficacy compared to 5-HT2A or 5-HT2C. The phenethylamines had low to mid micromolar affinities and potencies at the transporters. These results demonstrate that these –NBOMe and –NBOH substituted phenethylamines have a biochemical pharmacology consistent with hallucinogenic activity, with little psychostimulant activity.

Original languageEnglish (US)
Pages (from-to)27-34
Number of pages8
JournalBiochemical Pharmacology
Volume158
DOIs
StatePublished - Dec 1 2018

Fingerprint

Receptor, Serotonin, 5-HT2C
Phenethylamines
Receptor, Serotonin, 5-HT2A
Assays
Lysergic Acid Diethylamide
Pharmacology
Serotonin
Receptor, Serotonin, 5-HT2B
Norepinephrine Plasma Membrane Transport Proteins
Hallucinogens
Serotonin Plasma Membrane Transport Proteins
Dopamine Plasma Membrane Transport Proteins
Receptor, Serotonin, 5-HT1A
Inositol Phosphates
Phenol
Binding Sites
Toxicity
Cells
Pharmaceutical Preparations
2-(4-iodo-2,5-dimethoxyphenyl)-N-(2-methoxybenzyl)ethanamine

Keywords

  • 2-(((4-Iodo-2,5-dimethoxyphenethyl)amino)methyl)phenol (25I-NBOH) (PubChem CID: 10001761)
  • 2-(2,5-Dimethoxy-4-methylphenyl)-N-(2-methoxybenzyl)ethanamine (25D-NBOMe) (PubChem CID: 118536027)
  • 2-(2,5-Dimethoxy-4-nitrophenyl)-N-(2-methoxybenzyl)ethanamine) (25N-NBOMe) (PubChem CID: 118536028)
  • 2-(2,5-Dimethoxyphenyl)-N-(2-methoxybenzyl)ethanamine (25H-NBOMe) (PubChem CID: 121230760)
  • 2-(4-Ethyl-2,5-dimethoxyphenyl)-N-(2-methoxybenzyl)ethanamine (25E-NBOMe) (PubChem CID: 121230757)
  • Drug abuse
  • Lysergic acid diethylamide (LSD)
  • NBOMe
  • Serotonin receptor
  • Substituted phenethylamine

ASJC Scopus subject areas

  • Biochemistry
  • Pharmacology

Cite this

Neurochemical pharmacology of psychoactive substituted N-benzylphenethylamines : High potency agonists at 5-HT2A receptors. / Eshleman, Amy J.; Wolfrum, Katherine M.; Reed, John F.; Kim, Sunyoung O.; Johnson, Robert A.; Janowsky, Aaron.

In: Biochemical Pharmacology, Vol. 158, 01.12.2018, p. 27-34.

Research output: Contribution to journalArticle

Eshleman, Amy J. ; Wolfrum, Katherine M. ; Reed, John F. ; Kim, Sunyoung O. ; Johnson, Robert A. ; Janowsky, Aaron. / Neurochemical pharmacology of psychoactive substituted N-benzylphenethylamines : High potency agonists at 5-HT2A receptors. In: Biochemical Pharmacology. 2018 ; Vol. 158. pp. 27-34.
@article{87007f712baf4ef9ae70c1befb92addc,
title = "Neurochemical pharmacology of psychoactive substituted N-benzylphenethylamines: High potency agonists at 5-HT2A receptors",
abstract = "The use of new psychoactive substituted 2,5-dimethoxy-N-benzylphenethylamines is associated with abuse and toxicity in the United States and elsewhere and their pharmacology is not well known. This study compares the mechanisms of action of 2-(2,5-dimethoxy-4-methylphenyl)-N-(2-methoxybenzyl)ethanamine (25D-NBOMe), 2-(4-ethyl-2,5-dimethoxyphenyl)-N-(2-methoxybenzyl)ethanamine (25E-NBOMe), 2-(2,5-dimethoxyphenyl)-N-(2-methoxybenzyl)ethanamine (25H-NBOMe), 2-(((4-iodo-2,5-dimethoxyphenethyl)amino)methyl)phenol (25I-NBOH); and 2-(2,5-dimethoxy-4-nitrophenyl)-N-(2-methoxybenzyl)ethanamine) (25N-NBOMe) with hallucinogens and stimulants. Mammalian cells heterologously expressing 5-HT1A, 5-HT2A, 5-HT2B or 5-HT2C receptors, or dopamine, serotonin or norepinephrine transporters (DAT, SERT and NET, respectively) were used to assess drug affinities at radioligand binding sites. Potencies and efficacies were determined using [35S]GTPγS binding assays (5-HT1A), inositol-phosphate accumulation assays (5-HT2A 5-HT2B and 5-HT2C), and uptake and release assays (transporters). The substituted phenethylamines were very low potency and low efficacy agonists at the 5-HT1A receptor. 25D-NBOMe, 25E-NBOMe, 25H-NBOMe, 25I-NBOH and 25N-NBOMe had very high affinity for, and full efficacy at, 5-HT2A and 5-HT2C receptors. In the 5-HT2A receptor functional assay, 25D-NBOMe, 25E-NBOMe, 25I-NBOH and 25N-NBOMe had subnanomolar to low nanomolar potencies similar to (+)lysergic acid diethylamide (LSD) while 25H-NBOMe had lower potency, similar to serotonin. At the 5-HT2C receptor, four had very high potencies, similar to LSD and serotonin, while 25H-NBOMe had lower potency. At the 5-HT2B receptor, the compounds had lower affinity, potency and efficacy compared to 5-HT2A or 5-HT2C. The phenethylamines had low to mid micromolar affinities and potencies at the transporters. These results demonstrate that these –NBOMe and –NBOH substituted phenethylamines have a biochemical pharmacology consistent with hallucinogenic activity, with little psychostimulant activity.",
keywords = "2-(((4-Iodo-2,5-dimethoxyphenethyl)amino)methyl)phenol (25I-NBOH) (PubChem CID: 10001761), 2-(2,5-Dimethoxy-4-methylphenyl)-N-(2-methoxybenzyl)ethanamine (25D-NBOMe) (PubChem CID: 118536027), 2-(2,5-Dimethoxy-4-nitrophenyl)-N-(2-methoxybenzyl)ethanamine) (25N-NBOMe) (PubChem CID: 118536028), 2-(2,5-Dimethoxyphenyl)-N-(2-methoxybenzyl)ethanamine (25H-NBOMe) (PubChem CID: 121230760), 2-(4-Ethyl-2,5-dimethoxyphenyl)-N-(2-methoxybenzyl)ethanamine (25E-NBOMe) (PubChem CID: 121230757), Drug abuse, Lysergic acid diethylamide (LSD), NBOMe, Serotonin receptor, Substituted phenethylamine",
author = "Eshleman, {Amy J.} and Wolfrum, {Katherine M.} and Reed, {John F.} and Kim, {Sunyoung O.} and Johnson, {Robert A.} and Aaron Janowsky",
year = "2018",
month = "12",
day = "1",
doi = "10.1016/j.bcp.2018.09.024",
language = "English (US)",
volume = "158",
pages = "27--34",
journal = "Biochemical Pharmacology",
issn = "0006-2952",
publisher = "Elsevier Inc.",

}

TY - JOUR

T1 - Neurochemical pharmacology of psychoactive substituted N-benzylphenethylamines

T2 - High potency agonists at 5-HT2A receptors

AU - Eshleman, Amy J.

AU - Wolfrum, Katherine M.

AU - Reed, John F.

AU - Kim, Sunyoung O.

AU - Johnson, Robert A.

AU - Janowsky, Aaron

PY - 2018/12/1

Y1 - 2018/12/1

N2 - The use of new psychoactive substituted 2,5-dimethoxy-N-benzylphenethylamines is associated with abuse and toxicity in the United States and elsewhere and their pharmacology is not well known. This study compares the mechanisms of action of 2-(2,5-dimethoxy-4-methylphenyl)-N-(2-methoxybenzyl)ethanamine (25D-NBOMe), 2-(4-ethyl-2,5-dimethoxyphenyl)-N-(2-methoxybenzyl)ethanamine (25E-NBOMe), 2-(2,5-dimethoxyphenyl)-N-(2-methoxybenzyl)ethanamine (25H-NBOMe), 2-(((4-iodo-2,5-dimethoxyphenethyl)amino)methyl)phenol (25I-NBOH); and 2-(2,5-dimethoxy-4-nitrophenyl)-N-(2-methoxybenzyl)ethanamine) (25N-NBOMe) with hallucinogens and stimulants. Mammalian cells heterologously expressing 5-HT1A, 5-HT2A, 5-HT2B or 5-HT2C receptors, or dopamine, serotonin or norepinephrine transporters (DAT, SERT and NET, respectively) were used to assess drug affinities at radioligand binding sites. Potencies and efficacies were determined using [35S]GTPγS binding assays (5-HT1A), inositol-phosphate accumulation assays (5-HT2A 5-HT2B and 5-HT2C), and uptake and release assays (transporters). The substituted phenethylamines were very low potency and low efficacy agonists at the 5-HT1A receptor. 25D-NBOMe, 25E-NBOMe, 25H-NBOMe, 25I-NBOH and 25N-NBOMe had very high affinity for, and full efficacy at, 5-HT2A and 5-HT2C receptors. In the 5-HT2A receptor functional assay, 25D-NBOMe, 25E-NBOMe, 25I-NBOH and 25N-NBOMe had subnanomolar to low nanomolar potencies similar to (+)lysergic acid diethylamide (LSD) while 25H-NBOMe had lower potency, similar to serotonin. At the 5-HT2C receptor, four had very high potencies, similar to LSD and serotonin, while 25H-NBOMe had lower potency. At the 5-HT2B receptor, the compounds had lower affinity, potency and efficacy compared to 5-HT2A or 5-HT2C. The phenethylamines had low to mid micromolar affinities and potencies at the transporters. These results demonstrate that these –NBOMe and –NBOH substituted phenethylamines have a biochemical pharmacology consistent with hallucinogenic activity, with little psychostimulant activity.

AB - The use of new psychoactive substituted 2,5-dimethoxy-N-benzylphenethylamines is associated with abuse and toxicity in the United States and elsewhere and their pharmacology is not well known. This study compares the mechanisms of action of 2-(2,5-dimethoxy-4-methylphenyl)-N-(2-methoxybenzyl)ethanamine (25D-NBOMe), 2-(4-ethyl-2,5-dimethoxyphenyl)-N-(2-methoxybenzyl)ethanamine (25E-NBOMe), 2-(2,5-dimethoxyphenyl)-N-(2-methoxybenzyl)ethanamine (25H-NBOMe), 2-(((4-iodo-2,5-dimethoxyphenethyl)amino)methyl)phenol (25I-NBOH); and 2-(2,5-dimethoxy-4-nitrophenyl)-N-(2-methoxybenzyl)ethanamine) (25N-NBOMe) with hallucinogens and stimulants. Mammalian cells heterologously expressing 5-HT1A, 5-HT2A, 5-HT2B or 5-HT2C receptors, or dopamine, serotonin or norepinephrine transporters (DAT, SERT and NET, respectively) were used to assess drug affinities at radioligand binding sites. Potencies and efficacies were determined using [35S]GTPγS binding assays (5-HT1A), inositol-phosphate accumulation assays (5-HT2A 5-HT2B and 5-HT2C), and uptake and release assays (transporters). The substituted phenethylamines were very low potency and low efficacy agonists at the 5-HT1A receptor. 25D-NBOMe, 25E-NBOMe, 25H-NBOMe, 25I-NBOH and 25N-NBOMe had very high affinity for, and full efficacy at, 5-HT2A and 5-HT2C receptors. In the 5-HT2A receptor functional assay, 25D-NBOMe, 25E-NBOMe, 25I-NBOH and 25N-NBOMe had subnanomolar to low nanomolar potencies similar to (+)lysergic acid diethylamide (LSD) while 25H-NBOMe had lower potency, similar to serotonin. At the 5-HT2C receptor, four had very high potencies, similar to LSD and serotonin, while 25H-NBOMe had lower potency. At the 5-HT2B receptor, the compounds had lower affinity, potency and efficacy compared to 5-HT2A or 5-HT2C. The phenethylamines had low to mid micromolar affinities and potencies at the transporters. These results demonstrate that these –NBOMe and –NBOH substituted phenethylamines have a biochemical pharmacology consistent with hallucinogenic activity, with little psychostimulant activity.

KW - 2-(((4-Iodo-2,5-dimethoxyphenethyl)amino)methyl)phenol (25I-NBOH) (PubChem CID: 10001761)

KW - 2-(2,5-Dimethoxy-4-methylphenyl)-N-(2-methoxybenzyl)ethanamine (25D-NBOMe) (PubChem CID: 118536027)

KW - 2-(2,5-Dimethoxy-4-nitrophenyl)-N-(2-methoxybenzyl)ethanamine) (25N-NBOMe) (PubChem CID: 118536028)

KW - 2-(2,5-Dimethoxyphenyl)-N-(2-methoxybenzyl)ethanamine (25H-NBOMe) (PubChem CID: 121230760)

KW - 2-(4-Ethyl-2,5-dimethoxyphenyl)-N-(2-methoxybenzyl)ethanamine (25E-NBOMe) (PubChem CID: 121230757)

KW - Drug abuse

KW - Lysergic acid diethylamide (LSD)

KW - NBOMe

KW - Serotonin receptor

KW - Substituted phenethylamine

UR - http://www.scopus.com/inward/record.url?scp=85054191820&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85054191820&partnerID=8YFLogxK

U2 - 10.1016/j.bcp.2018.09.024

DO - 10.1016/j.bcp.2018.09.024

M3 - Article

C2 - 30261175

AN - SCOPUS:85054191820

VL - 158

SP - 27

EP - 34

JO - Biochemical Pharmacology

JF - Biochemical Pharmacology

SN - 0006-2952

ER -