Structure-Activity Relationship of Truncated 4'-Selenonucleosides: A₃ Adenosine Receptor Activity and Binding...

Area of Science:

• Medicinal Chemistry
• Pharmacology
• Computational Chemistry

Background:

• The A3 adenosine receptor (A3AR) is a therapeutic target for various diseases.
• Nucleoside analogs are explored for their potential as receptor ligands.
• Structural modifications of nucleosides can alter their interaction with target receptors.

Purpose of the Study:

• To investigate the structure-activity relationships (SAR) of truncated 4 omino-selenonucleosides as A3AR ligands.
• To identify novel compounds with high affinity and specific activity at the A3AR.
• To elucidate the binding interactions of these compounds with the A3AR using computational methods.

Main Methods:

• Synthesis of a series of truncated 4 omino-selenonucleosides.
• Evaluation of binding affinities and functional activities at the human A3AR (hA3AR).
• Computational docking studies to analyze ligand-receptor interactions.

Main Results:

• All synthesized compounds demonstrated selective and significant binding to the hA3AR.
• Compounds 6l (Ki = 5.2 nM) and 6m (Ki = 5.7 nM) exhibited the highest binding affinities.
• Compound 6m, a representative N6-cyclopropyl analog, functioned as a partial agonist, unlike antagonist truncated 4 omino-oxo and 4 omino-thio nucleosides.
• Docking studies revealed a unique interaction of 6m with Thr94 in the A3AR binding pocket.

Conclusions:

• Truncated 4 omino-selenonucleosides represent a promising class of selective A3AR modulators.
• Compound 6m displays unique partial agonist activity and specific binding interactions, suggesting therapeutic potential.
• This research deepens the understanding of A3AR ligand design and identifies novel lead compounds for drug development.