Cell
January 26, 2017
Daniel Wacker, Sheng Wang, J. Mccorvy et al.
466 citations
The hallucinogen LSD binds to the human serotonin receptor 5-HT2B, and its crystal structure reveals conformational rearrangements that accommodate LSD, explaining the selectivity of its diethylamide group. LSD dissociates very slowly from both 5-HT2BR and 5-HT2AR, a key receptor for its psychoactive effects. Molecular dynamics simulations suggest that a 'lid' formed by extracellular loop 2 (EL2) at the binding pocket entrance may cause LSD's slow binding kinetics. A mutation that increases this lid's mobility greatly speeds up LSD's binding and selectively reduces LSD-mediated β-arrestin2 recruitment, providing a molecular explanation for LSD's actions at human serotonin receptors.
Science
January 27, 2022
Dongmei Cao, Jing Yu, Huan Wang et al.
306 citations
Drugs targeting the human serotonin 2A receptor (5-HT2AR) are used for neuropsychiatric diseases, but many have hallucinogenic effects. Structures of 5-HT2AR complexed with psilocin, LSD, serotonin, and lisuride reveal that serotonin and psilocin show a second binding mode. This insight enabled design of the psychedelic IHCH-7113 and several 5-HT2AR β-arrestin–biased agonists that displayed antidepressant-like activity in mice without hallucinogenic effects. These structures provide a foundation for designing safe, nonhallucinogenic psychedelic analogs with therapeutic potential.
Chemical Reviews
November 30, 2023
Wenwen Duan, Dongmei Cao, Sheng Wang et al.
62 citations
Psychedelics such as psilocybin activate the serotonin 2A receptor (5-HT2AR) to produce hallucinogenic effects, and clinical trials show they can act as rapid-acting, long-lasting antidepressants. However, there is a need for rationally designed 5-HT2AR agonists with optimal pharmacological profiles to unlock therapeutic potential and identify safer, nonhallucinogenic drug candidates. This Perspective reviews structure-activity relationships of existing 5-HT2AR agonists by chemical classification and discusses recent structural-level advances in molecular pharmacology. Encouraging clinical outcomes have spurred drug discovery efforts to develop novel agonists with improved subtype selectivity and signaling bias, potentially yielding safer antidepressants. Structure-based methods and functional selectivity-directed screening could accelerate these efforts.
Neuron
October 9, 2024
Luyu Fan, Youwen Zhuang, Hongyu Wu et al.
6 citations
LSD dissociates extremely rapidly from the dopamine D1 receptor, driven by the flexibility of extracellular loop 2. Cryo-electron microscopy structures reveal a distinctive binding mode with the ergoline moiety oriented toward transmembrane helix 4. G protein binding stabilizes the extracellular loop 2 conformation, which markedly slows LSD's dissociation rate. These kinetic and structural insights clarify how LSD engages dopamine receptors and how G protein coupling versus β-arrestin coupling is determined, advancing understanding of GPCR dynamics and signal transduction.
Journal of Medicinal Chemistry
October 14, 2025
Rongyan Li, Hong Yan, Yujin Chen et al.
1 citation
New compounds designed to activate the serotonin 2A receptor without causing hallucinations show antidepressant effects in mice. Building on the structures of the antipsychotic aripiprazole and a previously reported lead compound, two series of novel 5-HT2A partial agonists were synthesized and tested. Several compounds demonstrated potent activity in G protein coupling and β-arrestin2 recruitment assays. One compound, 28c, reduced depressive-like behavior in the mouse tail-suspension test without producing head-twitch responses, a rodent correlate of hallucinogenic effects. These results add to the growing collection of nonhallucinogenic 5-HT2A agonists that could potentially provide rapid and enduring antidepressant effects.