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
Biochemical Pharmacology September 25, 2018 DOI: 10.1016/j.bcp.2018.09.024 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | In vitro pharmacology study Peer reviewed |
|---|---|
| Population | Mammalian cells heterologously expressing serotonin receptors (5-HT1A, 5-HT2A, 5-HT2B, 5-HT2C) or dopamine, serotonin, and norepinephrine transporters (DAT, SERT, NET) |
| Measures | radioligand binding assays, [35S]GTPγS binding assays (5-HT1A), inositol-phosphate accumulation assays (5-HT2A, 5-HT2B, 5-HT2C), uptake and release assays (DAT, SERT, NET) |
| Topics | Serotonin |
| Key points | The substituted phenethylamines tested had very high affinity and full efficacy at 5-HT2A and 5-HT2C receptors, with 25D-NBOMe, 25E-NBOMe, 25I-NBOH, and 25N-NBOMe showing subnanomolar to low nanomolar 5-HT2A potency similar to LSD, while 25H-NBOMe was less potent, similar to serotonin. The authors conclude this biochemical profile is consistent with hallucinogenic activity and little psychostimulant activity. |
Abstract
&NA; 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]GTP&ggr;S 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.
Comparable studies
Other preclinical and animal studies on serotonin, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo Mice | 2021 | Observational cohort | |
| Neurotoxicity of the psychedelic amphetamine, methylenedioxymethamphetamine. Rats (implied by typical neurochemical study context) | 1987 | Experimental study | |
| Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors In vitro and in vivo (rodent) models | 2023 | Experimental study | |
| 3,4-Methylenedioxymethamphetamine and 3,4-methylenedioxyamphetamine destroy serotonin terminals in rat brain: quantification of neurodegeneration by measurement of [3H]paroxetine-labeled serotonin uptake sites. Rat brain | 1987 | Animal experiment | |
| Comparison of the monoamine transporters from human and mouse in their sensitivities to psychostimulant drugs Human and mouse dopamine, norepinephrine, and serotonin transporters expressed in cells | 2006 | In vitro laboratory study |
Citations in the library
Cited by 43
- Designer drugs: mechanism of action and adverse effects Archives of Toxicology April 1, 2020
- Structure–Activity Relationships for Psilocybin, Baeocystin, Aeruginascin, and Related Analogues to Produce Pharmacological Effects in Mice ACS Pharmacology & Translational Science November 2, 2022
- NBOMes–Highly Potent and Toxic Alternatives of LSD Frontiers in Neuroscience February 26, 2020
- Serotonin 2A Receptor (5-HT2AR) Agonists: Psychedelics and Non-Hallucinogenic Analogues as Emerging Antidepressants Chemical Reviews November 30, 2023
- Molecular and clinical aspects of potential neurotoxicity induced by new psychoactive stimulants and psychedelics Experimental Neurology June 4, 2021
and 38 more in the library
Cites 20
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- Crystal structure of an LSD-bound human serotonin receptor Cell January 26, 2017
- Receptor interaction profiles of novel N-2-methoxybenzyl (NBOMe) derivatives of 2,5-dimethoxy-substituted phenethylamines (2C drugs). Neuropharmacology December 1, 2015
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- Effects of the hallucinogen 2,5-dimethoxy-4-iodophenethylamine (2C-I) and superpotent N-benzyl derivatives on the head twitch response. Neuropharmacology February 1, 2014
and 15 more in the library