Structure–Activity Relationship Analysis of Psychedelics in a Rat Model of Asthma Reveals the Anti-Inflammatory Pharmacophore,ACS Pharmacology & Translational Science

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Structure–Activity Relationship Analysis of Psychedelics in a Rat Model of Asthma Reveals the Anti-Inflammatory Pharmacophore
ACS Pharmacology & Translational Science ( IF 4.9 ) Pub Date : 2020-08-13 , DOI: 10.1021/acsptsci.0c00063
Thomas W Flanagan ₁ , Gerald B Billac ₁ , Alexus N Landry ₁ , Melaine N Sebastian ₁ , Stephania A Cormier ₂ , Charles D Nichols ₁

Affiliation

Psychedelic drugs can exert potent anti-inflammatory effects. However, anti-inflammatory effects do not appear to correlate with behavioral activity, suggesting different underlying mechanisms. We hypothesized that the distinct structural features of psychedelics underlie functionally selective mechanisms at the target 5-HT_2A receptor to elicit maximal anti-inflammatory effects. In order to test this hypothesis, we developed a new rat-based screening platform for allergic asthma. Next, we investigated 21 agonists at the 5-HT_2A receptor from the three primary chemotypes (phenylalkylamine, ergoline, and tryptamine) for their ability to prevent airways hyperresponsiveness as a measure of pulmonary inflammation. Furthermore, we assessed each drug for in vitro activation of the canonical signaling pathway, calcium mobilization, from the 5-HT_2A receptor. We find that the drug 2,5-dimethoxyphenethylamine (2C-H) represents the pharmacophore for anti-inflammatory activity and identify structural modifications that are either permissive or detrimental to anti-inflammatory activity. Additionally, there is no correlation between the ability of a particular psychedelic to activate intracellular calcium mobilization and to prevent the symptoms of asthma or with behavioral potencies. Our results support the notions that specific structural features mediate functional selectivity underlying anti-inflammatory activity and that relevant receptor activated pathways necessary for anti-inflammatory activity are different from canonical signaling pathways. Our results inform on the nature of interactions between ligands at the 5-HT_2A receptor as they relate to anti-inflammatory activity and are crucial for the development of new 5-HT_2A receptor agonists for anti-inflammatory therapeutics in the clinic that may be devoid of behavioral activity.

中文翻译：

致幻剂在哮喘大鼠模型中的结构-活性关系分析揭示了抗炎药效团

迷幻药可以发挥有效的抗炎作用。然而，抗炎作用似乎与行为活动无关，表明不同的潜在机制。我们假设致幻剂的独特结构特征是针对目标 5-HT _2A受体的功能选择机制的基础，以引发最大的抗炎作用。为了检验这一假设，我们开发了一种新的基于大鼠的过敏性哮喘筛查平台。接下来，我们研究了来自三种主要化学类型（苯烷基胺、麦角林和色胺）的 21 种 5-HT _2A受体激动剂，了解它们预防气道高反应性（作为肺部炎症指标）的能力。此外，我们还评估了每种药物对 5-HT _2A受体的经典信号通路（钙动员）的体外激活作用。我们发现药物 2,5-二甲氧基苯乙胺 (2C-H) 代表抗炎活性的药效团，并确定了允许或有害抗炎活性的结构修饰。此外，特定致幻剂激活细胞内钙动员的能力与预防哮喘症状或行为效力之间不存在相关性。我们的结果支持这样的观点，即特定的结构特征介导抗炎活性的功能选择性，并且抗炎活性所需的相关受体激活途径不同于典型的信号传导途径。我们的结果揭示了 5-HT _2A受体配体之间相互作用的性质，因为它们与抗炎活性有关，并且对于开发用于临床抗炎治疗的新 5-HT _2A受体激动剂至关重要。缺乏行为活动。

更新日期：2020-08-13

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