Agonists for the adenosine A(1) receptor with tunable residence time: a case for nonribose 4-Amino-6-aryl-5-cyano-2-thiopyrimidines

Medicinal Chemistr

Optimization of Peptide Linker-based Fluorescent Ligands for the Histamine H1 Receptor

The histamine H1 receptor (H1R) has recently been implicated in mediating cell proliferation and cancer progression, therefore high affinity H1R-selective fluorescent ligands are desirable tools for further investigation of this behaviour in vitro and in vivo. We previously reported a H1R fluorescent ligand, bearing a peptide-linker, based on antagonist VUF13816 and sought to further explore structure-activity relationships (SARs) around the linker, orthostere and fluorescent moieties. Here, we report a series of high affinity H1R fluorescent ligands varying in peptide linker composition, orthosteric targeting moiety and fluorophore. Incorporation of a boron-dipyrromethene (BODIPY) 630/650™-based fluorophore conferred high binding affinity to our H1R fluorescent ligands, remarkably overriding linker SAR observed in corresponding unlabeled congeners. Compound 31a, both potent and subtype-selective, enabled H1R visualization using confocal microscopy at a concentration of 10 nM. Molecular docking of 31a with the human H1R predicts the optimized peptide linker makes interactions with key residues in the receptor

Agonists for the Adenosine A₁ Receptor with Tunable Residence Time. A Case for Nonribose 4‑Amino-6-aryl-5-cyano-2-thiopyrimidines

We report the synthesis and evaluation of previously unreported 4-amino-6-aryl-5-cyano-2-thiopyrimidines as selective human adenosine A₁ receptor (hA₁AR) agonists with tunable binding kinetics, this without affecting their nanomolar affinity for the target receptor. They show a very diverse range of kinetic profiles (from 1 min (compound <b>52</b>) to 1 h (compound <b>43</b>)), and their structure–affinity relationships (SAR) and structure–kinetics relationships (SKR) were established. When put in perspective with the increasing importance of binding kinetics in drug discovery, these results bring new evidence of the consequences of affinity-only driven selection of drug candidates, that is, the potential elimination of slightly less active compounds that may display preferable binding kinetics

Synthesis and Characterization of a Bidirectional Photoswitchable Antagonist Toolbox for Real-Time GPCR Photopharmacology

Noninvasive methods to modulate G protein-coupled receptors (GPCRs) with temporal and spatial precision are in great demand. Photopharmacology uses photons to control <i>in situ</i> the biological properties of photoswitchable small-molecule ligands, which bodes well for chemical biological precision approaches. Integrating the light-switchable configurational properties of an azobenzene into the ligand core, we developed a bidirectional antagonist toolbox for an archetypical family A GPCR, the histamine H₃ receptor (H₃R). From 16 newly synthesized photoswitchable compounds, VUF14738 (<b>28</b>) and VUF14862 (<b>33</b>) were selected as they swiftly and reversibly photoisomerize and show over 10-fold increased or decreased H₃R binding affinities, respectively, upon illumination at 360 nm. Both ligands combine long thermal half-lives with fast and high photochemical <i>trans</i>-/<i>cis</i> conversion, allowing their use in real-time electrophysiology experiments with oocytes to confirm dynamic photomodulation of H₃R activation in repeated second-scale cycles. VUF14738 and VUF14862 are robust and fatigue-resistant photoswitchable GPCR antagonists suitable for spatiotemporal studies of H₃R signaling