• Article

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

Citation

Elmore, J. S., Decker, A. M., Sulima, A., Rice, K. C., Partilla, J. S., Blough, B. E., & Baumann, M. H. (2018). Comparative neuropharmacology of N-(2-methoxybenzyl)-2,5-dimethoxyphenethylamine (NBOMe) hallucinogens and their 2C counterparts in male rats. Neuropharmacology. DOI: 10.1016/j.neuropharm.2018.02.033

Abstract

2,5-Dimethoxyphenethylamines (2C compounds) are 5-HT2A/2Creceptor agonists that induce hallucinogenic effects. N-methoxybenzylation of 2C compounds markedly increases their affinity for 5-HT2Areceptors, 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-HT2A/2Cagonist 1-(4-iodo-2,5-dimethoxyphenyl)propan-2-amine (DOI). Compounds were tested in vitro using 5-HT2Areceptor 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-HT2A-mediated behaviors were assessed. NBOMes displayed higher affinity for 5-HT2Areceptors 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-HT2Aantagonist (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-HT2Areceptor were significantly correlated with potencies to induce BMC but not WDS. Our findings show that NBOMes are highly potent 5-HT2Aagonists in rats, similar to effects in mice, and consistent with the reported hallucinogenic effects in human users.