Structure-Based Approaches to Ligands for G-Protein-Coupled Adenosine and P2Y Receptors, from Small Molecules to Nanoconjugates

Abstract

Adenosine receptor (ARs) and P2Y receptors (P2YRs) that respond to extracellular nucleosides/tides are associated with new directions for therapeutics. The X-ray structures of the A 2A AR complexes with agonists and antagonists are examined in relationship to the G protein-coupled receptor (GPCR) superfamily and applied to drug discovery. Much of the data on AR ligand structure from early SAR studies, now is explainable from the A 2A AR X-ray crystallography. The ligand-receptor interactions in related GPCR complexes can be identified by means of modeling approaches, e.g. molecular docking. Thus, molecular recognition in binding and activation processes has been studied effectively using homology modeling and applied to ligand design. Virtual screening has yielded new nonnucleoside AR antagonists, and existing ligands have been improved with knowledge of the receptor interactions. New agonists are being explored for CNS and peripheral therapeutics based on in vivo activity, such as chronic neuropathic pain. Ligands for receptors more distantly related to the X-ray template, i.e. P2YRs, have been introduced and are mainly used as pharmacological tools for elucidating the physiological role of extracellular nucleotides. Other ligand tools for drug discovery include fluorescent probes, radioactive probes, multivalent probes, and functionalized nanoparticles.

Selectivity is species-dependent: Characterization of standard agonists and antagonists at human, rat, and mouse adenosine receptors

“…A medicinal chemical approach to develop A 3 AR antagonists that are active across species has recently been successfully pursued by Jacobson and coworkers who modified the ribose moiety so that the affinity stayed unaltered but the efficacy disappeared [84].…”

The purinergic neurotransmitter revisited: A single substance or multiple players?

“…Strategies that are currently used by medicinal chemists in search of purinergic drugs include development of 1) selective agonist and antagonist ligands for the P2X and P2Y receptors that respond to extracellular nucleotides and for the adenosine receptors (Jacobson 2013), 2) inhibitors of extracellular catabolism of purines, and 3) modulators of nucleotide and nucleoside transport (Burnstock, 2013d). Such drugs would be beneficial in treating organ system-specific aberrations in purinergic neurotransmission by increasing or decreasing local concentrations of purinergic neurotransmitters at target cells, by inhibiting or accelerating neurotransmitter clearance at neuroeffector junctions, by affecting mechanisms of storage and release of neurotransmitters or by modulating the postjunctional responses to released neurotransmitters.…”

Peripheral Adenosine A3 Receptor Activation Causes Regulated Hypothermia in Mice That Is Dependent on Central Histamine H1 Receptors

“…Use of Adora3 2/2 mice conclusively demonstrated a role for A 3 AR in triggering mouse mast cell degranulation , whereas the A 3 AR may not be important in human mast cell degranulation (Auchampach et al, 1997;Gomez et al, 2011;Rudich et al, 2012). The availability of potent, specific mouse A 3 AR agonists (Jacobson, 2013) allowed us to investigate the hypothermia induced by A 3 AR agonists and the contributing mechanisms.…”