Adenosine receptors and cardiovascular disease: the adenosine-1 receptor (A1) and A1 selective ligands

Area of Science:

• Biochemistry
• Pharmacology
• Cardiovascular Medicine

Background:

• Adenosine acts as a universal metabolite against metabolic/oxidative stress.
• Clinical applications of adenosine are restricted, primarily to cardiovascular indications like paroxysmal supraventricular tachycardia.
• Four adenosine receptor subtypes mediate adenosine's effects, presenting therapeutic targets for various disorders.

Purpose of the Study:

• To review the development and clinical limitations of adenosine receptor subtype-selective ligands.
• To highlight the challenges in developing subtype-selective therapies, including structural and signaling complexities.
• To discuss the preclinical and clinical development of adenosine subtype-1 (A1) receptor ligands for cardiovascular disorders.

Main Methods:

• Review of existing literature on adenosine receptor pharmacology.
• Analysis of challenges in developing selective ligands due to receptor structure and signaling differences.
• Discussion of specific A1 receptor ligands (agonists, antagonists, enhancers) and their therapeutic potential.

Main Results:

• Despite broad physiological roles, clinical use of adenosine and its subtype-selective ligands is limited.
• Lack of X-ray receptor structures and species/tissue variations hinder selective ligand development.
• Several A1 receptor ligands, including agonists (CVT-510, CVT-2759), antagonists (BG9719/CVT-124), and enhancers (PD81723), are under preclinical or clinical investigation.

Conclusions:

• Adenosine receptor subtype-selective ligands, particularly for A1, hold significant therapeutic potential for cardiovascular diseases.
• Overcoming challenges in ligand selectivity and understanding receptor-effector coupling are crucial for clinical translation.
• Further preclinical and clinical evaluation of A1 receptor modulators is warranted for various cardiovascular pathologies.