Joshua S. Elmore, A. Decker, A. Sulima
Nov 1, 2018
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1
Influential Citations
40
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Quality indicators
Journal
Neuropharmacology
Abstract
&NA; 2,5‐Dimethoxyphenethylamines (2C compounds) are 5‐HT2A/2C receptor agonists that induce hallucinogenic effects. N‐methoxybenzylation of 2C compounds markedly increases their affinity for 5‐HT2A 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‐HT2A/2C agonist 1‐(4‐iodo‐2,5‐dimethoxyphenyl)propan‐2‐amine (DOI). Compounds were tested in vitro using 5‐HT2A 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‐HT2A‐mediated behaviors were assessed. NBOMes displayed higher affinity for 5‐HT2A 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‐HT2A 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‐HT2A receptor were significantly correlated with potencies to induce BMC but not WDS. Our findings show that NBOMes are highly potent 5‐HT2A 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’. Graphical abstract Figure. No caption available. Highlights25C‐NBOMe and 25I‐NBOMe are 30‐fold more potent at rat 5‐HT2A receptors when compared to 2C‐C and 2C‐I.NBOMe compounds are more potent than 2‐C compounds at inducing wet dog shakes (WDS) and back muscle contractions (BMC).WDS and BMC produced by NBOMe are reversed by the 5‐HT2A antagonist M100907.NBOMe compounds are ultrapotent 5‐HT2A agonists in rats, consistent with their powerful hallucinogenic effects in humans.