The incorporation of photoswitches into the molecular structure of peptides and proteins enables their dynamic photocontrol in complex biological systems. Here, a perfluorinated azobenzene derivative triggered by amber light was site-specifically conjugated to cysteines in a helical peptide by perfluoroarylation chemistry. In response to the photoisomerization (trans!cis) of the conjugated azobenzene with amber light, the secondary structure of the peptide was modulated from a disorganized into an amphiphilic helical structure.

Recently, investigations of the complex mechanisms of allostery have led to a deeper understanding of G protein‐coupled receptor (GPCR) activation and signaling processes. In this context, muscarinic acetylcholine receptors (mAChRs) are highly relevant due to their exemplary role in the study of allosteric modulation. In this work, we compare and discuss two sets of putatively dualsteric ligands, which were designed to connect carbachol to different types of allosteric ligands. We chose derivatives of TBPB [1‐(1′‐(2‐tolyl)‐1,4′‐bipiperidin‐4‐yl)‐1H‐benzo[d]imidazol‐2(3H)‐one] as M1‐selective putative bitopic ligands, and derivatives of benzyl quinolone carboxylic acid (BQCA) as an M1 positive allosteric modulator, varying the distance between the allosteric and orthosteric building blocks. Luciferase protein complementation assays demonstrated that linker length must be carefully chosen to yield either agonist or antagonist behavior. These findings may help to design biased signaling and/or different extents of efficacy.

Classical psychedelics are a group of hallucinogens which trigger non‐ordinary states of consciousness through activation of the 5‐HT2A receptor (5‐HT2AR) in the brain. However, the exact mechanism of how 5‐HT2AR agonism alters perception remains elusive. When studying receptor signaling, tools which work at the same spatiotemporal resolution as the receptor are exceptionally useful. To create such a tool, we designed a set of photoswitchable ligands based on the classical psychedelic N,N‐dimethyltryptamine (DMT). By incorporation of the DMT‐indole ring into the photoswitchable system, we obtained red‐shifted ligands which can be operated by visible light. Among these azo‐DMTs, compound 2 h (“Photo‐DMT”) stands out as its cis isomer exhibits DMT like activity while the trans isomer acts as weak partial agonist. Such a cis‐on “efficacy switch” substantially expands the pharmacological toolbox to investigate the complex mechanisms of 5‐HT2AR signaling.

Neurochemistry The photomodulation of the 5‐HT2A receptor by a light‐controllable N,N‐dimethyltryptamine derivative is reported by Michael Decker et al. in their Communication (e202203034).

Ottergemsesteenweg 460, 9000 Ghent (Belgien)[ + ] Diese Autoren haben zu gleichen Teilen zu der Arbeit beigetragen.