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 DOI: 10.1039/d5cp01252j via PubMed
Summary
AI-generated from the abstractA new photoswitchable compound, PQ-azo-N,N-DMT, was computationally designed to improve upon an earlier version. It binds tightly to the 5-HT2A receptor, maintains key interactions similar to LSD, shows good membrane permeability, and absorbs red-shifted light for visible-spectrum photocontrol. This offers precise spatio-temporal control over receptor activation, which could help clarify the role of hallucinatory effects in antidepressant drug development.
Study at a glance
| Characteristics | Computational study Peer reviewed |
|---|---|
| Key finding | The photoswitch PQ-azo-N,N-DMT (34) shows improved features over azo-N,N-DMT (1), including tight binding to 5-HT2AR, retention of LSD-like interactions, positive membrane permeability, and strong red-shifted absorption for visible-light 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.