9 research outputs found
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 A<sub>1</sub> 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
A<sub>1</sub> receptor (hA<sub>1</sub>AR) 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 H<sub>3</sub> receptor (H<sub>3</sub>R). 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 H<sub>3</sub>R 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 H<sub>3</sub>R
activation in repeated second-scale cycles. VUF14738 and VUF14862
are robust and fatigue-resistant photoswitchable GPCR antagonists
suitable for spatiotemporal studies of H<sub>3</sub>R signaling