“Photo‐Adrenalines”: Photoswitchable β2‐Adrenergic Receptor Agonists as Molecular Probes for the Study of Spatiotemporal Adrenergic Signaling

β2‐adrenergic receptor (β2‐AR) agonists are used for the treatment of asthma and chronic obstructive pulmonary disease, but also play a role in other complex disorders including cancer, diabetes and heart diseases. As the cellular and molecular mechanisms in various cells and tissues of the β2‐AR remain vastly elusive, we developed tools for this investigation with high temporal and spatial resolution. Several photoswitchable β2‐AR agonists with nanomolar activity were synthesized. The most potent agonist for β2‐AR with reasonable switching is a one‐digit nanomolar active, trans‐on arylazopyrazole‐based adrenaline derivative and comprises valuable photopharmacological properties for further biological studies with high structural accordance to the native ligand adrenaline.β2‐adrenergic receptor agonists are used for the treatment of asthma, but also play a role in heart diseases. Several photoswitchable β2‐receptor agonists with nanomolar activity were synthesized and one adrenaline derivative is a one‐digit nanomolar, trans‐on, full agonist for the β2‐receptor. It represents a novel molecular probe for biological studies with high structural similarity to native adrenaline. image Deutsche Forschungsgemeinschaft http://dx.doi.org/10.13039/501100001659Elitenetzwerk Bayern http://dx.doi.org/10.13039/501100008848Studienstiftung des Deutschen Volkes http://dx.doi.org/10.13039/50110000435

Enlightening the 'spirit molecule' : photomodulation of the 5-HT2A receptor by a light-controllable N,N-dimethyltryptamine derivative

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

Novel BQCA‐ and TBPB‐Derived M 1 Receptor Hybrid Ligands: Orthosteric Carbachol Differentially Regulates Partial Agonism

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 M-1-selective putative bitopic ligands, and derivatives of benzyl quinolone carboxylic acid (BQCA) as an M-1 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

Amber Light Control of Peptide Secondary Structure by a Perfluoroaromatic Azobenzene Photoswitch

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