Neurochemical pharmacology of psychoactive substituted N-benzylphenethylamines: High potency agonists at 5-HT2A receptors - PubMed (original) (raw)

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

Amy J Eshleman et al. Biochem Pharmacol. 2018 Dec.

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.

Published by Elsevier Inc.

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Conflict of interest statement

Conflict of interest

All authors declare that they have no conflicts of interest.

Figures

Figure 1.

Figure 1.

Chemical structures of 25D-NBOMe, 25E-NBOMe, 25H-NBOMe, 25I-NBOH, 25N-NBOMe, 5-HT, LSD and DOM.

Figure 2.

Figure 2.

Agonist activity of -NBOMe phenethylamines at recombinant 5-HT1A, 5-HT2A, 5-HT2B and 5-HT2C receptors. All data were normalized to the maximal effect of 5-HT, which was measured on each experimental day. A. 5-HT1A [35S]GTPγS binding. N=3–7 independent experiments conducted with duplicate determinations. B. 5-HT2A agonist IP-1 assay. N=3–4 independent experiments conducted with duplicate determinations. C. 5-HT2B IP-1 assay. N=4–6 independent experiments conducted with duplicate determinations. D. 5-HT2C IP-1 assay. N=3–4 independent experiments conducted with duplicate determinations. Data shown are mean ± sem.

Figure 3.

Figure 3.

Correlation of affinities and agonist potencies of substituted phenethylamines at 5-HT1A, 5-HT2A, 5-HT2B and 5-HT2C receptors. The linear regression for the data in each graph is shown. A. 5-HT1A affinities as measured with [3H]8-OH-DPAT binding vs 5-HT1A potencies as measured using [35S]GTPγS binding. Spearman r=0.19, p>0.05. B. 5-HT2A affinities as measured with [125I]DOI binding vs 5-HT2A potencies as measured using the IP-1 assay. Spearman r=0.72, p=0.01. C. 5-HT2B affinities as measured with [3H]5-HT binding vs 5-HT2B potencies as measured using the IP-1 assay. Spearman r=0.76, p<0.05. D. 5-HT2C affinities as measured with [125I]DOI binding vs 5-HT2C potencies as measured with IP-1 assay. Spearman r=0.67, p<0.05. Values for 2C-C, 2C-D, 2C-E, 2C-I, 2C-T-2 and DOC are from [23]

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