Tuck Jeremy R, Dunlap Lee E, Khatib Yara A, Hatzipantelis Cassandra J, Weiser Novak Sammy, Rahn Rachel M, Davis Alexis R, Mosswood Adam, Vernier Anna M M, Fenton Ethan M, Aarrestad Isak K, Tombari Robert J, Carter Samuel J, Deane Zachary, Wang Yuning, Sheridan Arlo, Gonzalez Monica A, Avanes Arabo A, Powell Noel A, Chytil Milan, Engel Sharon, Fettinger James C, Jenkins Amaya R, Carlezon William A, Nord Alex S, Kangas Brian D, Rasmussen Kurt, Liston Conor, Manor Uri, Olson David E
Chemistry and Chemical Biology Graduate Program, University of California, Davis, CA 95616.
Institute for Psychedelics and Neurotherapeutics, University of California, Davis, CA 95616.
Proc Natl Acad Sci U S A. 2025 Apr 22;122(16):e2416106122. doi: 10.1073/pnas.2416106122. Epub 2025 Apr 14.
Decreased dendritic spine density in the cortex is a key pathological feature of neuropsychiatric diseases including depression, addiction, and schizophrenia (SCZ). Psychedelics possess a remarkable ability to promote cortical neuron growth and increase spine density; however, these compounds are contraindicated for patients with SCZ or a family history of psychosis. Here, we report the molecular design and de novo total synthesis of (+)-JRT, a structural analogue of lysergic acid diethylamide (LSD) with lower hallucinogenic potential and potent neuroplasticity-promoting properties. In addition to promoting spinogenesis in the cortex, (+)-JRT produces therapeutic effects in behavioral assays relevant to depression and cognition without exacerbating behavioral and gene expression signatures relevant to psychosis. This work underscores the potential of nonhallucinogenic psychoplastogens for treating diseases where the use of psychedelics presents significant safety concerns.
皮质中树突棘密度降低是包括抑郁症、成瘾和精神分裂症（SCZ）在内的神经精神疾病的关键病理特征。致幻剂具有促进皮质神经元生长和增加树突棘密度的显著能力；然而，这些化合物对患有SCZ或有精神病家族史的患者是禁忌的。在此，我们报告了（+）-JRT的分子设计和从头全合成，它是麦角酸二乙酰胺（LSD）的结构类似物，具有较低的致幻潜力和强大的促进神经可塑性的特性。除了促进皮质中的树突棘生成外，（+）-JRT在与抑郁症和认知相关的行为试验中产生治疗效果，而不会加剧与精神病相关的行为和基因表达特征。这项工作强调了非致幻性精神可塑性药物在治疗使用致幻剂存在重大安全问题的疾病方面的潜力。
