Coumarins and adenosine receptors: New perceptions in structure-affinity relationships

Area of Science:

• Medicinal Chemistry
• Pharmacology
• Drug Discovery

Background:

• Adenosine receptors (ARs) play crucial roles in various physiological and pharmacological processes.
• Selective modulation of AR subtypes offers therapeutic potential for diverse diseases.

Purpose of the Study:

• To discover and develop novel, potent, and selective AR ligands utilizing a coumarin scaffold.
• To synthesize and evaluate 3-phenylcarboxamidocoumarins for their affinity towards human AR subtypes.

Main Methods:

• Synthesis of a series of 3-phenylcarboxamidocoumarins.
• Radioligand binding assays for A1, A2A, and A3 AR subtypes.
• Adenylyl cyclase assay for A2B AR.
• Receptor-driven molecular modeling.

Main Results:

• Compound 26 emerged as the most promising candidate.
• Compound 26 exhibited significant selectivity for the A3 AR subtype (hA1/hA3 selectivity of 42, Ki = 2.4 μm).
• Molecular modeling provided insights into binding and selectivity, guiding further optimization.

Conclusions:

• Compound 26 possesses drug-like properties.
• The developed coumarin-based ligands show potential for selective modulation of adenosine receptors.
• Further optimization based on molecular modeling is warranted for therapeutic development.