A. Eshleman, Katherine M. Wolfrum, J. Reed
Dec 1, 2018
Citations
2
Influential Citations
44
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Quality indicators
Journal
Biochemical Pharmacology
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.