Department of Psychiatry, University of California San Diego, 9500 Gilman Drive, La Jolla, CA, 92093-0804, USA; Research Service, VA San Diego Healthcare System, 3350 La Jolla Village Dr., San Diego, CA, 92161, USA.
Department of Psychiatry, University of California San Diego, 9500 Gilman Drive, La Jolla, CA, 92093-0804, USA.
Neuropharmacology. 2019 Jan;144:368-376. doi: 10.1016/j.neuropharm.2018.10.037. Epub 2018 Oct 29.
In recent years, rigid analogs of phenylalkylamine hallucinogens have appeared as recreational drugs. Examples include 2-(8-bromo-2,3,6,7-tetrahydrobenzo[1,2-b:4,5-b']difuran-4-yl)ethan-1-amine (2C-B-FLY) and 1-(8-bromobenzo[1,2-b;4,5-b']difuran-4-yl)-2-aminopropane (Bromo-DragonFLY, DOB-DFLY). Although some rigid compounds such as DOB-DFLY reportedly have higher potency than their non-rigid counterparts, it is not clear whether the same is true for 2C-B-FLY and other tetrahydrobenzodifurans. In the present study, the head twitch response (HTR), a 5-HT receptor-mediated behavior induced by serotonergic hallucinogens, was used to assess the effects of 2,5-dimethoxy-4-bromoamphetamine (DOB) and its α-desmethyl homologue 2,5-dimethoxy-4-bromophenethylamine (2C-B), as well as their benzodifuranyl and tetrahydrobenzodifuranyl analogs, in C57BL/6J mice. DOB (ED = 0.75 μmol/kg) and 2C-B (ED = 2.43 μmol/kg) induced the HTR. The benzodifurans DOB-DFLY (ED = 0.20 μmol/kg) and 2C-B-DFLY (ED = 1.07 μmol/kg) had significantly higher potency than DOB and 2C-B, respectively. The tetrahydrobenzodifurans DOB-FLY (ED = 0.67 μmol/kg) and 2C-B-FLY (ED = 1.79 μmol/kg), by contrast, were approximately equipotent with their non-rigid counterparts. Three novel tetrahydrobenzodifurans (2C-I-FLY, 2C-E-FLY and 2C-EF-FLY) were also active in the HTR assay but had relatively low potency. In summary, the in vivo potency of 2,5-dimethoxyphenylalkylamines is enhanced when the 2- and 5-methoxy groups are incorporated into aromatic furan rings, whereas potency is not altered if the methoxy groups are incorporated into dihydrofuran rings. The potency relationships for these compounds in mice closely parallel the human hallucinogenic data. The high potency of DOB-DFLY is probably linked to the presence of two structural features (a benzodifuran nucleus and an α-methyl group) known to enhance the potency of phenylalkylamine hallucinogens.
近年来，刚性苯乙胺类致幻剂类似物已作为娱乐性药物出现。其中包括 2-(8-溴-2,3,6,7-四氢苯并[1,2-b:4,5-b']二呋喃-4-基)乙-1-胺（2C-B-FLY）和 1-(8-溴苯并[1,2-b;4,5-b']二呋喃-4-基)-2-氨基丙烷（Bromo-DragonFLY，DOB-DFLY）。尽管一些刚性化合物，如 DOB-DFLY，据称比它们的非刚性对应物具有更高的效力，但 2C-B-FLY 和其他四氢苯并二呋喃是否也是如此尚不清楚。在本研究中，头部抽搐反应（HTR），一种由 5-羟色胺能致幻剂诱导的 5-HT 受体介导的行为，用于评估 2,5-二甲氧基-4-溴苯丙胺（DOB）及其α-去甲基同系物 2,5-二甲氧基-4-溴苯乙胺（2C-B），以及它们的苯并二呋喃和四氢苯并二呋喃类似物，在 C57BL/6J 小鼠中的作用。DOB（ED=0.75μmol/kg）和 2C-B（ED=2.43μmol/kg）诱导 HTR。苯并二呋喃 DOB-DFLY（ED=0.20μmol/kg）和 2C-B-DFLY（ED=1.07μmol/kg）的效力明显高于 DOB 和 2C-B。相比之下，四氢苯并二呋喃 DOB-FLY（ED=0.67μmol/kg）和 2C-B-FLY（ED=1.79μmol/kg）与它们的非刚性对应物具有相近的效力。三种新型四氢苯并二呋喃（2C-I-FLY、2C-E-FLY 和 2C-EF-FLY）在 HTR 测定中也具有活性，但效力相对较低。总之，当 2-和 5-甲氧基被并入芳族呋喃环时，2,5-二甲氧基苯乙胺的体内效力增强，而当甲氧基被并入二氢呋喃环时，效力不会改变。这些化合物在小鼠中的效力关系与人类致幻数据非常相似。DOB-DFLY 的高效力可能与存在两个已知增强苯乙胺类致幻剂效力的结构特征（苯并二呋喃核和α-甲基）有关。
