2025 Theses Doctoral

Design and Synthesis of Quipazine Analogs for Programmable Control of Psychedelic Effects

Yang, Yilun

Psychoactive drugs targeting the 5-HT2A receptor exhibit profound effects on perception, emotion and cognition, and have shown therapeutic potential in treating neuropsychiatric disorders such as depression and anxiety. However, the clinical use of 5-HT2A receptor agonists is limited by several conditions, one of which is the psychedelic effect they produce.

To better understand how to potentially regulate these effects, we focused on the design of compounds with programmable psychedelic intensity through fine-tuning the 5-HT2A receptor signaling efficacy. We turned to the source that drives the psychedelic effects of serotonergic psychedelics, the 5-HT2A receptor. By modifying the scaffold of quipazine, we aimed to control the psychedelic intensity by tuning different levels of 5-HT2A signaling efficacy within the quipazine analog series, and thus provide design guidelines for developing desirable pharmacological agents with varying degree of psychedelic effects.