Rewiring Receptor Activation: Mechanistic Insights into Toggle Switch Modulation by 25CN-NBx Compounds
Vito F. Palmisano, Micaela Vidal−sánchez, Juan J. Nogueira
ACS Chemical Neuroscience February 18, 2026 DOI: 10.1021/acschemneuro.6c00023 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Molecular dynamics simulations Peer reviewed |
|---|---|
| Keywords | Dihedral angle Molecular dynamics Receptor Molecular mechanics Modulation music Molecular switch Biophysics Signalling |
| Key points | Bulky substitutions on the N-benzyl ring of 25CN-NBx compounds shift the position of W336 in the 5-HT2A receptor, affecting receptor activation and psychedelic signaling. |
Abstract
High Resolution Image Download MS PowerPoint Slide The development of new treatments for neuropsychiatric disorders relies on a deeper understanding of the molecular mechanisms behind psychedelic compounds, particularly how they differentiate between hallucinogenic and antidepressant effects. In this study, we explore by molecular dynamics simulations a series of 25CN-NBx compounds bound to the 5-HT 2A receptor. The simulations uncover that bulky substitutions on the N -benzyl ring cause a significant shift in the position of W336, a key toggle switch residue known to influence receptor activation and thought to play a crucial role in mediating psychedelic signaling. This result is confirmed through potential of mean force calculations along the toggle switch’s dihedral angle. End-state free energy calculations align closely with experimental data, showing that 25CN-NB-2-OH-3-Me and 25CN-NB-2-OH-5-MeO have the highest and lowest affinities, respectively, for the 5-HT 2A receptor. Further analysis indicates that when W336 adopts its negative dihedral state, it establishes stronger van der Waals interactions, stabilizing its contacts with residues F332 and I163─key players previously linked to receptor activation. Our findings provide a framework for understanding receptor activation and can be extended to other G protein-coupled receptors where the toggle switch is central to signal activation.