Molecular design of a therapeutic LSD analogue with reduced hallucinogenic potential

• 成果类型: Article
• 署名作者: Tuck, Jeremy R.; Dunlap, Lee E.; Khatib, Yara A.; Hatzipantelis, Cassandra J.; Novak, Sammy Weiser; 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 Jr, William A.; Nord, Alex S.; Kangas, Brian D.; Rasmussen, Kurt; Liston, Conor; Manor, Uri; Olson, David E.
• 署名单位: University of California System; University of California Davis; University of California System; University of California Davis; University of California System; University of California Davis; University of California System; University of California Davis; Salk Institute; Cornell University; Weill Cornell Medicine; Cornell University; Weill Cornell Medicine; University of California System; University of California Davis; University of California System; University of California Davis; Harvard University; Harvard University Medical Affiliates; McLean Hospital; University of California System; University of California Davis; University of California System; University of California Davis; University of California System; University of California Davis; University of California System; University of California San Diego; University of California System; University of California Davis
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-9656
• DOI: 10.1073/pnas.2416106122
• 发表日期: 2025-04-22
• 关键词: dendritic spine alterations; drug discovery; schizophrenia; psilocybin; cortex; antagonists; modulation; mechanisms; pathology; disorder

摘要

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.