Department of Neuroscience, Carleton University, Ottawa, ON K1S 5B6, Canada.
Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
Cell Rep. 2023 Mar 28;42(3):112203. doi: 10.1016/j.celrep.2023.112203. Epub 2023 Mar 6.
Hallucinations limit widespread therapeutic use of psychedelics as rapidly acting antidepressants. Here we profiled the non-hallucinogenic lysergic acid diethylamide (LSD) analog 2-bromo-LSD (2-Br-LSD) at more than 33 aminergic G protein-coupled receptors (GPCRs). 2-Br-LSD shows partial agonism at several aminergic GPCRs, including 5-HT, and does not induce the head-twitch response (HTR) in mice, supporting its classification as a non-hallucinogenic 5-HT partial agonist. Unlike LSD, 2-Br-LSD lacks 5-HT agonism, an effect linked to cardiac valvulopathy. Additionally, 2-Br-LSD produces weak 5-HT β-arrestin recruitment and internalization in vitro and does not induce tolerance in vivo after repeated administration. 2-Br-LSD induces dendritogenesis and spinogenesis in cultured rat cortical neurons and increases active coping behavior in mice, an effect blocked by the 5-HT-selective antagonist volinanserin (M100907). 2-Br-LSD also reverses the behavioral effects of chronic stress. Overall, 2-Br-LSD has an improved pharmacological profile compared with LSD and may have profound therapeutic value for mood disorders and other indications.
幻觉限制了迷幻药作为快速抗抑郁药的广泛治疗用途。在这里，我们对非致幻性麦角酸二乙酰胺（LSD）类似物 2-溴-LSD（2-Br-LSD）在 33 种以上的单胺能 G 蛋白偶联受体（GPCR）进行了分析。2-Br-LSD 在几种单胺能 GPCR 上显示部分激动作用，包括 5-HT，并且不会在小鼠中引起摇头反应（HTR），支持其作为非致幻性 5-HT 部分激动剂的分类。与 LSD 不同，2-Br-LSD 缺乏 5-HT 激动作用，这种作用与心脏瓣膜病有关。此外，2-Br-LSD 在体外产生弱的 5-HT β-arrestin 募集和内化，并且在重复给药后不会在体内诱导耐受。2-Br-LSD 诱导培养的大鼠皮质神经元的树突发生和棘突发生，并增加小鼠的积极应对行为，这种作用被 5-HT 选择性拮抗剂 volinanserin（M100907）阻断。2-Br-LSD 还能逆转慢性应激的行为效应。总的来说，与 LSD 相比，2-Br-LSD 的药理学特性得到了改善，它可能对情绪障碍和其他适应症具有深远的治疗价值。
