Kwan Alex C, Mantsch John R, McCorvy John D
Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY 14850, USA.
Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
Trends Pharmacol Sci. 2025 Aug 27. doi: 10.1016/j.tips.2025.07.017.
There is growing interest in developing psychedelic-inspired drugs for treating psychiatric disorders. However, identifying next-generation psychedelic analogs with ideal receptor selectivity and true therapeutic efficacy remains a major challenge. Recent progress has been driven by advances in determining agonist-induced biased signal transduction, high-content behavioral phenotyping via automated video analysis, drug-evoked structural neural remodeling, and activity-dependent gene expression. In this review, we outline a framework for evaluating psychedelics and non-hallucinogenic serotonin 2A (5-HT) receptor agonists. We critically examine current methods for assessing (A) agonism, (B) behavior, and (C) cellular plasticity. We highlight emerging techniques that may improve translation to humans. We contend that an effective discovery pipeline must align with specific experimental goals and incorporate multiple approaches to be successful for psychedelic drug development.
开发用于治疗精神疾病的受迷幻药启发的药物正引起越来越多的关注。然而，确定具有理想受体选择性和真正治疗效果的下一代迷幻类似物仍然是一项重大挑战。最近的进展得益于在确定激动剂诱导的偏向信号转导、通过自动视频分析进行的高内涵行为表型分析、药物诱发的结构性神经重塑以及活性依赖性基因表达等方面取得的进展。在这篇综述中，我们概述了一个评估迷幻药和非致幻性血清素2A（5-HT）受体激动剂的框架。我们批判性地审视了当前用于评估（A）激动作用、（B）行为和（C）细胞可塑性的方法。我们强调了可能改善向人类转化的新兴技术。我们认为，一个有效的发现流程必须与特定的实验目标相一致，并采用多种方法才能在迷幻药开发中取得成功。
