Adenosine receptors as therapeutic targets

Abstract

Adenosine receptors are major targets of caffeine, the most commonly consumed drug in the world. There is growing evidence that they could also be promising therapeutic targets in a wide range of conditions, including cerebral and cardiac ischaemic diseases, sleep disorders, immune and inflammatory disorders and cancer. After more than three decades of medicinal chemistry research, a considerable number of selective agonists and antagonists of adenosine receptors have been discovered, and some have been clinically evaluated, although none has yet received regulatory approval. However, recent advances in the understanding of the roles of the various adenosine receptor subtypes, and in the development of selective and potent ligands, as discussed in this review, have brought the goal of therapeutic application of adenosine receptor modulators considerably closer.

Figure 1. Adenosine receptor signalling pathways

Activation of the A₁ and A₃ adenosine receptors (ARs) inhibits adenylyl cyclase activity through activation of pertussis toxin-sensitive G_i proteins and results in increased activity of phospholipase C (PLC) via G_βγ subunits. Activation of the A_2A and A_2B ARs increases adenylyl cyclase activity through activation of G_s proteins. Activation of the A_2AAR to induce formation of inositol phosphates can occur under certain circumstances, possibly via the pertussis toxin-insensitive Gα15 and Gα16 proteins. A_2BAR-induced activation of PLC is through G_q proteins. All four subtypes of ARs can couple to mitogen-activated protein kinase (MAPK), giving them a role in cell growth, survival, death and differentiation. CREB, cAMP response element binding protein; DAG, diacylglycerol; IP₃, inositol 1,4,5-trisphosphate; PI3K, phosphatidylinositol 3-kinase; PIP₂, phosphatidylinositol-4,5-bisphosphate; PK, protein kinase; PLD, phospholipase D; NF-κB, nuclear factor-κB.

Figure 2. Adenosine receptor agonists

Adenosine receptor (AR) agonists acting at the A₁AR. K_i values for binding to ARs are given in TABLE 1.

Figure 3. Adenosine receptor agonists

a ∣ Adenosine receptor (AR) agonists acting at the A_2AAR. LUF5835 (EC₅₀ of 10 nM) is an atypical A_2BAR agonist. b ∣ AR agonists selective for the A₃AR. K_i values for binding to ARs are given in TABLE 1.

Figure 4. Adenosine receptor antagonists

Antagonists acting at the A₁ adenosine receptors (A₁ARs) and A_2AARs. K_i values for binding to the ARs are given in TABLE 1.

Figure 5. Adenosine receptor antagonists

Antagonists acting at the A_2B and A₃ ARs. Novartis compound has high affinity at human A_2B and A₃ ARs. K_i values for binding to the ARs are given in TABLE 1.

Figure 6. Examples of allosteric enhancers of the activity of adenosine receptor agonists

PD81,723 and T-62 enhance the activity of agonists acting at the A₁ adenosine receptor (A₁AR) and VUF5455 and DU124183 enhance the activity of agonists acting at the A₃ AR.

Figure 7. Novel disease targets for selective adenosine receptor ligands

Most promising prospects exist for treatment of arrhythmias, ischaemia of the heart and brain, pain, neurodegenerative diseases, sleep disorders, inflammation, diabetes, renal failure, cancer and glaucoma, and in cardiovascular imaging. High and intermediate levels of A₁ adenosine receptor (AR) expression were found in the brain, heart, adipose tissue, stomach, vas deferens, testis, spleen, kidney, aorta, liver, eye and bladder. The A_2AAR is highly expressed in the striatum, nucleus accumbens and olfactory tubercle. High and intermediate expression levels were also found in immune cells, heart, lung and blood vessels. The A_2B AR was generally expressed at low levels in almost all tissues. Rat testis has particularly high concentrations of A₃AR mRNA, with moderate levels in lung. The highest levels of human A₃AR mRNA have been found in lung and liver. A₃ARs have been detected in various tissues including testis, lung, kidney, placenta, heart, brain, spleen, liver, uterus, bladder, jejunum, aorta, proximal colon and eyes.