Computational design of an improved photoswitchable psychedelic based on light absorption, membrane permeation and protein binding.
Vito F Palmisano, Claudio Agnorelli, Shirin Faraji, Juan J Nogueira
Physical chemistry chemical physics : PCCP September 18, 2025 Peer reviewed DOI: 10.1039/d5cp01252j via PubMed
Summary
PQ-azo-N,N-DMT is a newly discovered photoswitchable compound that shows potential for antidepressant drug development. It binds tightly to the 5-HT2AR receptor, maintaining critical interactions similar to LSD, and demonstrates good membrane permeability. Additionally, it features a strong red-shifted absorption, enabling photocontrol in the visible spectrum. These characteristics suggest it may enhance the understanding of the hallucinatory effects of psychedelics and their therapeutic benefits.
Study at a glance
| Key finding | The new compound PQ-azo-N,N-DMT exhibits tight binding to the 5-HT2AR and retains important interactions of LSD while allowing for photocontrol. |
|---|
Abstract
Psychedelic compounds can induce rapid-acting and long-lasting antidepressant benefits. Understanding the role of their hallucinatory effects is crucial for shaping the future trajectory of antidepressant drug development. Photoswitchable compounds targeting the 5-HT2AR offer precise spatio-temporal control over the activation of different downstream pathways. In this work, we computationally discovered PQ-azo-N,N-DMT (34), a photoswitch with improved features compared to the previously synthesized azo-N,N-DMT (1). The new compound shows tight binding to the 5-HT2AR, retaining all important interactions of lysergic acid diethylamide (LSD), exhibits positive membrane permeability, and has a strong red-shifted absorption that would allow photocontrol in the visible spectrum.