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_2A/2C receptor agonists that induce hallucinogenic effects. N-methoxybenzylation of 2C compounds markedly increases their affinity for 5-HT_2A 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_2A/2C agonist 1-(4-iodo-2,5-dimethoxyphenyl)propan-2-amine (DOI). Compounds were tested in vitro using 5-HT_2A 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_2A-mediated behaviors were assessed. NBOMes displayed higher affinity for 5-HT_2A 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_2A 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_2A receptor were significantly correlated with potencies to induce BMC but not WDS. Our findings show that NBOMes are highly potent 5-HT_2A 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'.

Keywords: 5-HT(2A) receptor; Back muscle contractions; NBOMe; Wet dog shakes.

Figure 1

Chemical structures of 1-(4-iodo-2,5-dimethoxyphenyl)propan-2-amine (DOI); 2-(4-chloro-2,5-dimethoxyphenyl)ethanamine (2C-C), and its N-methoxybenzylated derivative 2-(4-chloro-2,5-dimethoxyphenyl)-N-[(2-methoxyphenyl)methyl]ethanamine (25C-NBOMe); and 2-(4-iodo-2,5-dimethoxyphenyl)ethanamine (2C-I), and its N-methoxybenzylated derivative 2-(4-iodo-2,5-dimethoxyphenyl)-N-[(2-methoxyphenyl)methyl]ethanamine (25I-NBOMe).

Figure 2

Dose-response effects of NBOMe compounds and their 2C analogs to inhibit binding of [³H]M100907 at 5-HT_2A receptors in rat brain tissue. Various concentrations of test compounds were incubated with 1 nM [³H]M100907, and assays were terminated using rapid filtration. Non-specific binding was determined in the presence of 10 µM ketanserin. Data are % inhibition of specific binding in the absence of added drug and are expressed as mean ± SEM for N=3 experiments performed in triplicate.

Figure 3

Dose-response effects of DOI (0.03–1.0 mg/kg, sc) on summed WDS and BMC in rats (panels A and B), and effects of 30 min pretreatment with 0.01–0.1 mg/kg M100907 (M100) or its vehicle (Veh) on behaviors induced by 1.0 mg/kg DOI (panels C and D). Rats were observed for 90 s every 15 min for 2 h post-injection, and the number of WDS and BMC was totaled. Data are mean ± SEM for N = 9 rats per group. * represents significant effects on behavior when compared to the corresponding vehicle (0 dose) or vehicle/vehicle (Veh/Veh) groups (Bonferroni, p<0.05).

Figure 4

Dose-response effects of 25C-NBOMe (0.01–0.3 mg/kg, sc) on summed WDS and BMC in rats (panels A and B), and effects of 30 min pretreatment with 0.1 mg/kg M100907 (M100) or its vehicle (Veh) on WDS and BMC induced by 0.03 mg/kg 25C-NBOMe (panels C and D). Rats were observed for 90 s every 15 min for 2 h post-injection, and the number of WDS and BMC was totaled. Data are mean ± SEM for N = 9 rats per group. * represents significant effects on behavior when compared to the corresponding vehicle (0 dose) or vehicle/vehicle (Veh/Veh) groups (Bonferroni, p<0.05).

Figure 5

Dose-response effects of 25I-NBOMe (0.01–0.3 mg/kg, sc) on summed WDS and BMC in rats (panels A and B), and effects of 30 min pretreatment with 0.1 mg/kg M100907 (M100) or its vehicle (Veh) on the WDS and BMC induced by 0.1 mg/kg 25I-NBOMe (panels C and D). Rats were observed for 90 s every 15 min for 2 h post-injection, and the number of WDS and BMC was totaled. Data are mean ± SEM for N = 9 rats per group. * represents significant effects on behavior when compared to the corresponding vehicle (0 dose) or vehicle/vehicle (Veh/Veh) groups (Bonferroni, p<0.05).

Figure 6

Dose-response effects of 2C-C (0.1–3.0 mg/kg, sc) on summed WDS and BMC in rats (panels A and B), and effects of 30 min pretreatment with 0.1 mg/kg M100907 (M100) or its vehicle (Veh) on the WDS and BMC induced by 0.3 mg/kg 2C-C. Rats were observed for 90 s every 15 min for 2 h post-injection, and the number of WDS and BMC was totaled. Data are mean ± SEM for N = 9 rats per group. * represents significant effects on behavior when compared to the corresponding vehicle (0 dose) or vehicle/vehicle (Veh/Veh) groups (Bonferroni, p<0.05).

Figure 7

Dose-response effects of 2C-I (0.1–3.0 mg/kg, sc) on summed WDS and BMC in rats (panels A and B), and effects of 30 min pretreatment with 0.1 mg/kg M100907 (M100) or its vehicle (Veh) on the WDS and BMC induced by 1.0 mg/kg 2C-I. Rats were observed for 90 s every 15 min for 2 h post-injection, and the number of WDS and BMC was totaled. Data are mean ± SEM for N = 9 rats per group. * represents significant effects on behavior when compared to the corresponding vehicle (0 dose) or vehicle/vehicle (Veh/Veh) groups (Bonferroni, p<0.05).