Abstract：
Psychedelics make up a group of psychoactive compounds that induce hallucinogenic effects by activating the serotonin 2A receptor (5-HT2AR). 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-HT2AR 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-HT2AR 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-HT2AR 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.
摘要：
迷幻药构成一组通过激活5-羟色胺2A受体(5-HT2AR)诱导致幻作用的精神活性化合物。临床试验表明，像psilocybin这样的传统迷幻物质是一类速效和持久的抗抑郁药。然而,迫切需要合理设计的具有最佳药理学特征的5-HT2AR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.本观点概述了现有5-HT2AR激动剂基于其化学分类的结构-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。迷幻药在抑郁症治疗中令人鼓舞的临床结果引发了药物发现的努力，旨在开发具有改善亚型选择性和信号偏向特性的新型5-HT2AR激动剂。可以作为更安全和潜在非致幻的抗抑郁药。通过利用基于结构的方法和功能选择性指导的筛选，可以显着加快这些努力。
