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-(2,5dimethoxyphenyl)-N-(2-methoxybenzyl)ethanamine (25H-NBOMe), 2-(((4-iodo-2,5dimethoxyphenethyl)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, 25HNBOMe, 25I-NBOH and 25N-NBOMe had very high affinity for, and full efficacy at, 5HT2A and 5-HT2C receptors. In the 5-HT2A receptor functional assay, 25D-NBOMe, 25ENBOMe, 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.

Designer drugs: mechanism of action and adverse effects

“…Psychedelic phenethylamine derivatives are mostly but not exclusively chemically modified at the phenyl ring. The introduction of an N-benzylmethoxy (''NBOMe'') group has been shown to increase the potency of the resulting derivatives (Eshleman et al 2018;Halberstadt 2017;Heim 2004;Rickli et al 2015c). The incorporation of 2 0 -and 5 0 -methoxy groups into rigid rings resulted in tetrahydrobenzodifuran and benzodifuran analogs that have been sold as designer drugs.…”

“…Similar to other psychedelics, substituted phenethylamines mainly interact with serotonergic receptors, with the highest affinity for 5-HT 2A receptors (Eshleman et al 2018;Kolaczynska et al 2019;Luethi et al 2018d;Rickli Fig. 8 Correlation between reported clinical potencies and in vitro human 5-HT 2A receptor affinities of a variety of psychedelics.…”

“…NBOMe derivatives have higher affinity for 5-HT 2A and 5-HT 2C receptors and lower affinity for 5-HT 1A receptors compared with their 2C analogs (Rickli et al 2015c). At 5-HT 2A receptors, 2C and NBOMe derivatives were shown to be partial or full agonists, depending on the functional in vitro assay (Eshleman et al 2014(Eshleman et al , 2018Jensen et al 2017;Kolaczynska et al 2019;Luethi et al 2018dLuethi et al , 2019cMoya et al 2007;Rickli et al 2015c). NBOMe derivatives and most 2C derivatives have been shown to be partial agonists at 5-HT 2B receptors (Eshleman et al 2018;Jensen et al 2017;Kolaczynska et al 2019;Luethi et al 2018d;Rickli et al 2015c).…”

NBOMes–Highly Potent and Toxic Alternatives of LSD

“…In vitro studies indicated that NBOMe compounds are ultrapotent and highly efficacious agonists of 5-HT 2A and 5-HT 2C receptors (Ki values in low nanomolar range), with more than 1000-fold selectivity for 5-HT 2A compared with 5-HT 1A . The compounds display higher affinity for 5-HT 2A receptors than their 2C counterparts and have markedly lower affinity, potency, and efficacy at the 5-HT 2B receptor than at 5-HT 2A or 5-HT 2C (Juncosa et al, 2013;Nichols et al, 2015;Rickli et al, 2015;Elmore et al, 2018;Eshleman et al, 2018). In addition, NBOMes have a significant affinity (Ki < 300 nM) for adrenergic α 1 receptors but not so H 1 -histamine, dopamine D 1 , D 2 , and D 3 receptors or the monoamine transporters DAT, NET, or SERT (Nichols et al, 2015;Elmore et al, 2018;Eshleman et al, 2018).…”

Identification of new NBOH drugs in seized blotter papers: 25B-NBOH, 25C-NBOH, and 25E-NBOH

“…Phenethylamines are agonists of the serotonin (5-HT, 5-hydroxytryptamine) receptors [4]. The N-benzyl substitution in phenethylamines (usually from the 2C-X family, such as 2C-I and 2C-B) improve the binding and functional activity in 5-HT receptors, with N-(2-hydroxybenzyl) substituted substances usually presenting the highest affinities to the 5-HT 2A receptor [4][5][6].…”