Serotonin 2A Receptor (5-HT2AR) Agonists: Psychedelics and Non-Hallucinogenic Analogues as Emerging Antidepressants,Chemical Reviews

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Serotonin 2A Receptor (5-HT2AR) Agonists: Psychedelics and Non-Hallucinogenic Analogues as Emerging Antidepressants
Chemical Reviews ( IF 51.4 ) Pub Date : 2023-11-30 , DOI: 10.1021/acs.chemrev.3c00375
Wenwen Duan ₁ , Dongmei Cao ₂ , Sheng Wang _{2,

3} , Jianjun Cheng _{1,

4}

Affiliation

Psychedelics make up a group of psychoactive compounds that induce hallucinogenic effects by activating the serotonin 2A receptor (5-HT_2AR). Clinical trials have demonstrated the traditional psychedelic substances like psilocybin as a class of rapid-acting and long-lasting antidepressants. However, there is a pressing need for rationally designed 5-HT_2AR agonists that possess optimal pharmacological profiles in order to fully reveal the therapeutic potential of these agonists and identify safer drug candidates devoid of hallucinogenic effects. This Perspective provides an overview of the structure–activity relationships of existing 5-HT_2AR agonists based on their chemical classifications and discusses recent advancements in understanding their molecular pharmacology at a structural level. The encouraging clinical outcomes of psychedelics in depression treatment have sparked drug discovery endeavors aimed at developing novel 5-HT_2AR agonists with improved subtype selectivity and signaling bias properties, which could serve as safer and potentially nonhallucinogenic antidepressants. These efforts can be significantly expedited through the utilization of structure-based methods and functional selectivity-directed screening.

中文翻译：

血清素 2A 受体 (5-HT2AR) 激动剂：迷幻药和非致幻类似物作为新兴抗抑郁药

迷幻药是一组精神活性化合物，通过激活血清素 2A 受体 (5-HT _2A R) 诱导致幻作用。临床试验表明，裸盖菇素等传统致幻物质是一类速效、长效的抗抑郁药。然而，迫切需要合理设计的具有最佳药理学特征的5-HT _2A R 激动剂，以充分揭示这些激动剂的治疗潜力并确定没有致幻作用的更安全的候选药物。本综述根据化学分类概述了现有 5-HT _2A R 激动剂的结构-活性关系，并讨论了在结构水平上理解其分子药理学的最新进展。致幻剂在抑郁症治疗中令人鼓舞的临床结果引发了药物发现工作，旨在开发新型 5-HT _2A R 激动剂，该激动剂具有改善的亚型选择性和信号偏向特性，可以作为更安全且潜在的非致幻性抗抑郁药。通过利用基于结构的方法和功能选择性定向筛选可以显着加快这些工作。

更新日期：2023-11-30

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