Exploring Adenosine Receptor Ligands: Potential Role in the Treatment of Cardiovascular Diseases

Abstract

Cardiovascular diseases remain the number one diseases affecting patients' morbidity and mortality. The adenosine receptors are G-protein coupled receptors which have been of interest for drugs target for the treatment of multiple diseases ranging from cardiovascular to neurological. Adenosine receptors have been connected to several biological pathways affecting the physiology and pathology of the cardiovascular system. In this review, we will cover the different adenosine receptor ligands that have been identified to interact with adenosine receptors and affect the vascular system. These ligands will be evaluated from clinical as well as medicinal chemistry perspectives with more emphasis on how structural changes in structure translate into ligand potency and efficacy. Adenosine receptors represent a novel therapeutic target for development of treatment options treating a wide variety of diseases, including vascular disease and obesity.

Keywords: atherosclerosis; cardiac death; myocardial infarction; vascular tone.

Figure 1

The role of adenosine receptors in vascular tone regulation. See text for details. A₁AR: adenosine A₁ receptor; A_2AAR: adenonsine A_2A receptor; AA: arachidonic acid; 20-HETE: 20-hydroxyeicosatetraenoic acid; EETs: epoxyeicosatrienoic acids; and DHETs: dihydroxyeicosatrienoic acids.

Figure 2

Structures of the adenosine A_2A receptor with (A) caffeine (PDB: 3RFM); (B) the antagonist ZM241385 (PDB: 3EML); and (C) the agonist CGS21680 (PDB: 4UG2). It has been shown that the extracellular loops play an important role in the agonist/antagonist interaction of compounds with the receptors. These crystal structures have been used to design novel small organic compounds which can be used to target the adenosine receptors.

Figure 3

Structure of (A) adenosine A₁ receptor bound with the covalent antagonist DU172 (PDB: 5UEN); (B) overlay of the A₁ (green) and A_2A (red) receptors showing the significant difference in the extracellular loop region (ECL) between the two receptors [26,27].

Figure 4

Structures of adenosine ligands which were evaluated in clinical trials. The therapeutic areas represented a range from cardiovascular to neurodegenerative diseases such as Parkinson’s disease [25]. For a more in-depth review, the reader is referred to a recent review [3].

Figure 5

The progression from xanthines, such as caffeine, to the novel compound istradefylline, which was recently approved for the use in Parkinson’s diseases.

Figure 6

Synthesis route of styrylxanthines such as istradyfilline.

Figure 7

The styrylxanthine scaffold is preferred for A_2A receptor binding when compared to the phenoxymethyl or phenylpropyl xanthines [31].

Figure 8

Structures of the phthalimide and istatin based compounds and their affinity for the adenosine receptors [32].

Figure 9

Structure of the 2-amiopyridine that was found to be a dual A₁/A_2A receptor [33].

Figure 10

Carbamate-based adenosine receptor antagonists [34].

Figure 11

Phenoxymethyl-xanthine derivatives which are dual A₁/A_2A antagonists [35].

Figure 12

Substitution on the styryl moiety with the phenoxymethyl side chain leads to dual A₁/A_2A receptor antagonists [35].

Figure 13

Docking of (A) istradyfilline (KW-6002) and the (B) phenoxymethyl-xanthine derivative in the adenosine A_2A receptor (3EML). The two compounds share a binding motif with the coordination with the water in the binding pocket of adenosine A_2A receptor.