PDF(Pubmed)
Abstract：
Serotonergic psychedelics are described to have activation of the serotonin 2A receptor (5-HT2A) as their main pharmacological action. Despite their relevance, the molecular mechanisms underlying the psychedelic effects induced by certain 5-HT2A agonists remain elusive. One of the proposed hypotheses is the occurrence of biased agonism, defined as the preferential activation of certain signaling pathways over others. This study comparatively monitored the efficiency of a diverse panel of 4-position-substituted (and N-benzyl-derived) phenylalkylamines to induce recruitment of β-arrestin2 (βarr2) or miniGαq to the 5-HT2A, allowing us to assess structure-activity relationships and biased agonism. All test compounds exhibited agonist properties with a relatively large range of both EC50 and Emax values. Interestingly, the lipophilicity of the 2C-X phenethylamines was correlated with their efficacy in both assays but yielded a stronger correlation in the miniGαq- than in the βarr2-assay. Molecular docking suggested that accommodation of the 4-substituent of the 2C-X analogues in a hydrophobic pocket between transmembrane helices 4 and 5 of 5-HT2A may contribute to this differential effect. Aside from previously used standard conditions (lysergic acid diethylamide (LSD) as a reference agonist and a 2 h activation profile to assess a compound\'s activity), serotonin was included as a second reference agonist, and the compounds\' activities were also assessed using the first 30 min of the activation profile. Under all assessed circumstances, the qualitative structure-activity relationships remained unchanged. Furthermore, the use of two reference agonists allowed for the estimation of both \"benchmark bias\" (relative to LSD) and \"physiology bias\" (relative to serotonin).
摘要：
血清素能迷幻药被描述为具有5-羟色胺2A受体（5-HT2A）的激活作为其主要药理作用。尽管它们具有相关性,某些5-HT2A激动剂诱导的迷幻作用的分子机制仍然难以捉摸。提出的假设之一是发生有偏见的激动，定义为某些信号通路优先于其他信号通路的激活。这项研究比较了一组不同的4位取代的（和N-苄基衍生的）苯基烷基胺的效率，以诱导β-arrestin2（βarr2）或miniGαq募集到5-HT2A，允许我们评估结构-活动关系和有偏见的激动。所有测试化合物都表现出具有相对大范围的EC50和Emax值的激动剂性质。有趣的是,2C-X苯乙胺的亲脂性与它们在两种测定中的功效相关,但在miniGαq-中的相关性强于βarr2-测定.分子对接表明，在5-HT2A的跨膜螺旋4和5之间的疏水袋中容纳2C-X类似物的4-取代基可能有助于这种差异效应。除了先前使用的标准条件(麦角酰二乙胺(LSD)作为参比激动剂和2小时激活曲线以评估化合物的活性),血清素作为第二种参考激动剂，和化合物的活性也使用活化曲线的前30分钟进行评估。在所有评估的情况下，定性结构-活动关系保持不变。此外，使用两种参考激动剂可以同时估计“基准偏倚”（相对于LSD）和“生理偏倚”（相对于5-羟色胺）。
