Designer Drug Research Unit, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, 21224, USA.
Center for Drug Discovery, Research Triangle Institute, Research Triangle Park, NC, 27709, USA.
Neuropharmacology. 2018 Nov;142:240-250. doi: 10.1016/j.neuropharm.2018.02.033. Epub 2018 Mar 1.
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'.
2,5-二甲氧基苯乙胺（2C 化合物）是 5-羟色胺受体激动剂，能引起致幻作用。2C 化合物的 N-甲氧基苄基化显著增加了它们对 5-羟色胺受体的亲和力，两种这样的类似物，2-(4-氯-2,5-二甲氧基苯基）-N-[(2-甲氧基苯基)甲基]乙胺（25C-NBOMe）和 2-(4-碘-2,5-二甲氧基苯基）-N-[(2-甲氧基苯基)甲基]乙胺（25I-NBOMe），已经出现在娱乐性药物市场中。在这里，我们研究了 25C-NBOMe 和 25I-NBOMe 在大鼠中的神经药理学特性，与它们的 2C 类似物和原型 5-羟色胺激动剂 1-(4-碘-2,5-二甲氧基苯基)丙-2-胺（DOI）进行了比较。使用 5-羟色胺受体结合和钙动员测定在体外测试化合物。对于体内实验，皮下（sc）给予 25C-NBOMe（0.01-0.3mg/kg）、25I-NBOMe（0.01-0.3mg/kg）、2-(4-氯-2,5-二甲氧基苯基）乙胺（2C-C）（0.1-3.0mg/kg）、2-(4-碘-2,5-二甲氧基苯基）乙胺（2C-I）（0.1-3.0mg/kg）和 DOI（0.03-1.0mg/kg），评估 5-羟色胺介导的行为。NBOMes 对 5-羟色胺受体的亲和力高于其 2C 对应物，但在功能测定中明显较弱。与 2C-C 和 2C-I 相比，25C-NBOMe 和 25I-NBOMe 更能诱导湿狗抖动（WDS）和背肌收缩（BMC）。选择性 5-羟色胺拮抗剂（R）-（2,3-二甲氧基苯基）{1-[2-（4-氟苯基）乙基]-4-哌啶基}甲醇（M100907）预处理可逆转所有激动剂产生的行为。有趣的是，在 5-羟色胺受体上的结合亲和力与诱导 BMC 的效力显著相关，但与诱导 WDS 的效力无关。我们的研究结果表明，NBOMes 在大鼠中是高度有效的 5-羟色胺激动剂，与在小鼠中的作用相似，并与报告的人类使用者的致幻作用一致。本文是题为“迷幻剂：新门，改变的观念”的特刊的一部分。
