Comparative neuropharmacology of N-(2-methoxybenzyl)-2,5-dimethoxyphenethylamine (NBOMe) hallucinogens and their 2C counterparts in male rats

Abstract

2,5-Dimethoxyphenethylamines (2C compounds) are 5-HT receptor agonists that induce hallucinogenic effects. N-methoxybenzylation of 2C compounds markedly increases their affinity for 5-HT receptors, and two such analogs, 2-(4-chloro-2,5-dimethoxyphenyl)-N-[(2-methoxyphenyl)methyl]ethanamine (25C-NBOMe) and 2-(4-iodo-2,5-dimethoxyphenyl)-N-[(2-methoxyphenyl)methyl]ethanamine (25I-NBOMe), have emerged in recreational drug markets. Here, we investigated the neuropharmacology of 25C-NBOMe and 25I-NBOMe in rats, as compared to their 2C analogs and the prototypical 5-HT agonist 1-(4-iodo-2,5-dimethoxyphenyl)propan-2-amine (DOI). Compounds were tested in vitro using 5-HT receptor binding and calcium mobilization assays. For in vivo experiments, 25C-NBOMe (0.01-0.3 mg/kg), 25I-NBOMe (0.01-0.3 mg/kg), 2-(4-chloro-2,5-dimethoxyphenyl)ethanamine (2C-C) (0.1-3.0 mg/kg), 2-(4-iodo-2,5-dimethoxyphenyl)ethanamine (2C-I) (0.1-3.0 mg/kg) and DOI (0.03-1.0 mg/kg) were administered subcutaneously (sc) to male rats, and 5-HT-mediated behaviors were assessed. NBOMes displayed higher affinity for 5-HT receptors than their 2C counterparts but were substantially weaker in functional assays. 25C-NBOMe and 25I-NBOMe were much more potent at inducing wet dog shakes (WDS) and back muscle contractions (BMC) when compared to 2C-C and 2C-I. Pretreatment with the selective 5-HT antagonist (R)-(2,3-dimethoxyphenyl){1-[2-(4-fluorophenyl)ethyl]-4-piperidinyl}methanol (M100907) reversed behaviors produced by all agonists. Interestingly, binding affinities at the 5-HT receptor were significantly correlated with potencies to induce BMC but not WDS. Our findings show that NBOMes are highly potent 5-HT agonists in rats, similar to effects in mice, and consistent with the reported hallucinogenic effects in human users. This article is part of the Special Issue entitled 'Psychedelics: New Doors, Altered Perceptions'.

Designer drugs: mechanism of action and adverse effects

“…At 5-HT 2C receptors, 2C derivatives were shown to be partial or full agonists (Eshleman et al 2014;Moya et al 2007), and NBOMe derivatives were shown to be full agonists (Eshleman et al 2018;Jensen et al 2017). Consistent with the in vitro findings, psychedelic phenethylamines were shown to induce 5-HT 2A -dependent behaviors in vivo, such as wet dog shakes, back muscle contractions, and a head twitch response (Elmore et al 2018;Fantegrossi et al 2005;Halberstadt et al 2020;Halberstadt and Geyer 2014). In addition to interactions with serotonergic receptors, phenethylamine psychedelics have been shown to interact with other monoaminergic targets, including adrenergic, dopaminergic, and histaminergic receptors, monoamine transporters, and MAOs (Eshleman et al 2018;Kolaczynska et al 2019;Luethi et al 2018d;Noble et al 2018;Rickli et al 2015c;Wagmann et al 2019a).…”

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

“…For parent compounds of 25D-NBOMe, 25E-NBOMe and 25I-NBOH at 5-HT 1A , 5-HT 2A and 5-HT 2C receptors, using the same assay conditions, 2C-D had affinities of 1630, 23.9 and 12.7 nM; 2C-E had affinities of 1190, 4.5, and 5.4 nM; and 2C-I had affinities of 970, 9.3, 10.2 nM, respectively [23]. Comparison of these values with Ki values for the corresponding – NBOMe and –NBOH analogs (Table 1) indicates that affinities for 5-HT 1A were decreased while 5-HT 2A affinities were increased 35–100 times by addition of –NBOMe and –NBOH moieties, and 5-HT 2C affinities were increased 10–18 times, similar to affinity shifts of other –NBOMe [41]. Thus the affinity selectivity for the 5-HT 2A receptor was increased with the N-benzyl additions.…”

Neurochemical and Behavioral Profiling in Male and Female Rats of the Psychedelic Agent 25I-NBOMe

“…Despite the widespread use of these compounds, and the effects reported in humans, there is a lack of knowledge about their behavioral or toxicological effects. The serotonergic psychedelic effects of this compound have been confirmed by behavioral responses such as head twitch in C57BL/6J mice (NBOMe 0.1-1 mg/kg, s.c.) (Halberstadt and Geyer, 2014), wet dog shakes, and back muscle contraction (0.01-3 mg/kg, s.c.) in rats (Elmore et al, 2018), and all these effects were prevented by the administration of the selective 5-HT2A antagonist M100907 (Halberstadt and Geyer, 2014;Elmore et al, 2018). Indeed, 25I-NBOMe timedependently and dose-dependently decreased locomotor activity in mice (Eshleman et al, 2014;Gatch et al, 2017) and showed full substitution of LSD in rats drug discrimination and more than 50% of appropriate responding in MDMA-trained rats (Eshleman et al, 2014).…”