• Article

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

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.

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. https://doi.org/10.1016/j.neuropharm.2018.02.033