Artículo destacado

Drug News & Perspectives
Vol. 16, No. 5, 2003, p. 283-289
ISSN 0214-0934
Copyright 2003 Prous Science, S.A.
CCC: 0214-0934/2003
http://www.prous.com

LOOKING AHEAD

The results obtained with pharmacological tools and genetically modified mice have indicated a number of potential therapeutic areas for drugs acting at adenosine receptors.

Adenosine Receptors as Targets for Drug Development

by Bertil B. Fredholm

Summary

Adenosine is a ubiquitous autacoid that acts on four defined receptors, named A₁, A_2A, A_2B and A₃. Although the biological activity of adenosine has been known for more than 70 years and the existence of specific receptors for more than 25 years, it is only now that the full potential for drug development is becoming clear. Among some of the conditions for which adenosine receptor-based therapy might be used are Parkinson's disease, hypoxia/ischemia, epilepsy, kidney disease and asthma. © 2003 Prous Science. All rights reserved.

Adenosine is a ubiquitous autacoid that acts on four defined receptors, named A₁, A_2A, A_2B and A₃.¹ Although the biological activity of adenosine has been known for more than 70 years² and the existence of specific receptors for more than 25 years,³ it is only now that the full potential for drug development is becoming clear.

Regulation of adenosine levels

In order to appreciate the potential role of drugs that target the adenosine receptors, we must first consider some facts about the regulation of the levels of the endogenous agonist (Fig. 1). Levels of adenosine are in the range of 30-300 nM in most extracellular fluids under basal conditions.^4,5 Then, at least 90% of the extracellular adenosine derives from intracellular sources, of which hydrolysis of AMP via 5¢-nucleotidase is the most important,⁶ but hydrolysis of S-adenosyl homocysteine also contributes. Extracellular and intracellular levels are usually rather similar because most cells possess efficient equilibrative transporters. Since there are also sodium-dependent transporters, and because adenosine is rapidly rephosphorylated (and deaminated) under normal situations, cytosolic concentrations are usually somewhat lower than the extracellular ones. This explains the finding that inhibi-tors of membrane transport usually increase extracellular adenosine levels. However, when intracellular adenosine production exceeds the rate of adenosine deamination and rephosphorylation, there is a concentration gradient from intra- to extracellular. Under such circumstances, membrane transport blockers would be expected to increase the intracellular adenosine concentration more than the extracellular level.^6-10

Fig. 1. Schematic representation of different pathways of regulation of extracellular adenosine. Abbreviations: ADO, adenosine; Hcy, L-homocysteine; AdoHcy, S-adenosyl homocysteine; SAM, S-adenosyl methionine; Ino, inosine.

Via several mechanisms, extracellular adenosine levels rise dramatically during hypoxia and ischemia (Fig. 2). This increase explains why adenosine is believed to play a particularly important role in hypoxia and ischemia (or whenever there is an imbalance bet-ween energy supply and demand). Under some circumstances, breakdown of extracellular ATP (and other adenine nucleotides), via a range of different enzymes,¹¹ can contribute significantly to overall levels of extracellular adenosine (Fig. 3). We still do not know precisely how ATP and other adenine nucleotides are released, but it seems likely that such release can be very important for regulation of extracellular adenosine in localized compartments. In particular, the profound rise in ATP, and hence in adenosine, that occurs following cell death means that organ trauma is associated with elevated adenosine.

Fig. 2. Mechanisms behind increased adenosine levels in hypoxia/ischemia. In particular, note that an energy deficiency reduces the activity of NaK-ATPase and, thereby, the Na gradient, so that the Na-dependent transporter can export rather than import adenosine. Abbreviations: ADO, adenosine; Hcy, L-homocysteine; AdoHcy, S-adenosyl homocysteine; SAM, S-adenosyl methionine.

Fig. 3. Different ways in which ATP may be released from cells, thereby contributing to extracellular adenosine levels.

Adenosine receptors

The four adenosine receptors all belong to the family of G-protein-coupled receptors.¹ A₁ and A₃ receptors most often activate pertussis toxin-sensitive G_i/o family of G-proteins. As seen in Figure 4, this initial event can affect several different signaling events, and the precise type of effect that is elicited will differ from cell to cell. By contrast, A_2A and A_2B receptors most often couple to the G_s family of G-proteins. The A_2A receptors in striatum couple to G_olf proteins,¹² but in other locations the different forms of G_s are the preferred partners. It should also be mentioned that when overexpressed, the adenosine receptors may also activate G_q and G_12/13 proteins, adding further dimensions to their signaling potential.

Fig. 4. Aspects of signaling via adenosine receptors. Abbreviations: PLC, phospholipase C; PI3K, phosphatidylinositol 3 kinase; MAP, mitogen-activated protein.

All four adenosine receptors are primarily activated by adenosine, but A₁ and A₃ receptors can also be stimulated by inosine.^13,14 However, inosine appears to be both less potent and less efficacious, indicating that under most conceivable circumstances adenosine is the important endogenous agonist. The interest in adenosine receptors is bolstered by the fact that A₁, A_2A and A_2B receptors are the target for the most widely used of all drugs, caffeine.¹⁵ By contrast, A₃ receptors are not affected by caffeine in concentrations reached by human caffeine consumption.

Drugs

Over the years, several drugs that act more or less selectively on adenosine receptors have been developed.^1,16 At A₁ receptors, some N⁶-substituted adenosine derivatives, including N⁶ cyclohexyl and cyclopentyl adenosine, show high affinity and selectivity. 2-chloro-N⁶ cyclopentyl adenosine ap-pears even more selective. 8-Cyclo-pentyl-1,3-dipropyl xanthine is quite selective as an A₁ receptor antagonist, even though an effect at A_2B receptors cannot be excluded. All these drugs are also useful radioligands.

At A_2A receptors, SCH-58261 is a highly selective antagonist, but it is not readily available, and hence the close relative ZM-241385 is more widely used. However, the latter compound suffers from the fact that it also has appreciable activity at A_2B receptors. CGS-21680 is widely used as a highly selective agonist at A_2A receptors, but has appreciable affinity for non-A_2A sites.¹ So far, the A_2B receptor has proved to be a difficult drug target, and highly selective agonists and antagonists are difficult to come by. In the case of A₃ receptors, the agonist Cl-IB-MECA has proved useful (but the related compound IB-MECA is not selective). There are also several com- pounds that show some selectivity for the human form of the A₃ receptor, but few if any compounds are useful in studies of A₃ receptors in nonhuman species.

Besides classic full agonists and competitive antagonists, some partial agonists and inverse agonists have been developed.¹⁷ Such compounds offer some possibilities for additional specificity of action. In particular, partial agonists would be expected to act as antagonists at sites where endogenous activation is high. Furthermore, they would be selective agonists at sites where there is little endogenous agonism, but where there is a high receptor number. Recently, PET ligands for adenosine receptor research have been developed; they could make it possible to determine, in humans, not only if there are differences in receptor density with disease, but also the receptor occupancy of possible therapeutic agents.¹⁸

It is also noteworthy that adenosine receptors may be targets for several drugs that are believed to have primarily other targets. This is true for barbiturates¹⁹ and for several drugs that are used as kinase inhibitors or inhibitors of adenylate cyclase.²⁰

Transgenic animals

The roles played by adenosine receptors in physiological and pathophysiological states can be inferred not only from studies using the above-mentioned drugs, but also from several recently developed transgenic animals. Mice that overexpress adenosine A₁ receptors show increased resistance to myocardial ischemia.²¹ Studies with an antisense construct against A₁ receptors suggested a role for A₁ receptors in asthma.²² Mice with a targeted disruption of A₁ receptors exhibit hyperalgesia and anxiety, and show a markedly different neural response to hypoxia.²³ In addition, these mice appear to be more susceptible to stress, since they tend to die younger even though the maximal life span and the initial growth are unaffected.²⁴ Mice that lack A₁ receptors have an in-creased blood pressure and urine production, and they lack tubuloglomerular feedback.²⁵ It has been suggested that adenosine A₁ receptors play a critically important role in the development of several organs including the brain.²⁶ It is therefore surprising that few if any major changes in the nervous system are observed in A₁ knockout mice.

The first knockout reported was of the A_2A receptor. The mouse reproduced normally, but had an increased blood pressure and heart rate. It also showed an increased aggregation of blood platelets. Although it was behaviorally normal in most respects, the A_2A knockout mouse was anxious and hyperaggressive. The mice in this study also showed behavior that indicate that A_2A receptor antagonists may be useful as antidepressants.²⁷ Very importantly, the behavioral stimulant effects of caffeine were lost in the mice.^28,29 A_2A receptor knockout mice also showed decreased sensitivity to peripheral painful stimuli,²⁸ indicating that A_2A receptors cause hyperalgesia.

Using another knockout mouse, it was found that A_2A receptors were important in controlling the extent of damage after ischemia.³⁰ These results were confirmed by the use of selective receptor antagonists. This A_2A knockout mouse also provided very strong evidence, supporting and extending previous results obtained with antagonists, that A_2A receptors can control the development of dopamine neuron degeneration³¹ and hence that A_2A antagonists may be an important therapeutic principle in Parkinson's disease.³² The profound role of A_2A receptors is further indicated by the finding that mice lacking A_2A receptors showed a decreased LTP response in the basal ganglia.³³ There is a tonic action of adenosine at A_2A receptors that is unmasked by blocking dopa-mine D₂ receptors, emphasizing the tight coupling between the two receptors.^34,35

The A_2A receptors play an important role in modulating lymphocyte function.^36,37 They also regulate ma-crophage responses, including their production of vascular endothelial growth factor (VEGF), but the VEGF response to hypoxia does not appear to be directly mediated by A_2A or A₃ receptors.³⁸ Nevertheless, adenosine acting on A_2A receptors appears to play an important role in wound healing and angiogenesis.³⁹

Judging from A₃ knockout mice, the adenosine A₃ receptors appear to play an important role in regulation of mediator release from mast cells and other immune cells.⁴⁰ This also has consequences for inflammatory pain, as it has been shown that the inflammation causing pain is reduced in A₃ knockout mice.⁴¹ The A₃ receptor also appears to play a role in blood pressure regulation.⁴² The A₃ receptor knockout mice also showed resistance to myo-cardial ischemia, although early preconditioning could be demonstrated in these mice⁴³ (by contrast, there is evidence that late preconditioning can be elicited by stimulating A₃ receptors).^44,45

Therapeutic possibilities

The results obtained with pharmacological tools and genetically modified mice have indicated a number of potential therapeutic areas for drugs acting at adenosine receptors. These will be briefly described below.

Parkinson's disease

There is interesting epidemiological evidence that the incidence of Parkinson's disease is inversely related to caffeine intake.⁴⁶ This fact together with a large body of experimental evidence in animals^31,47-50 and the extensive work demonstrating an intimate interrelationship between adenosine A_2A receptors and dopamine D₂ receptors in the basal ganglia of several species including humans^51,52 makes this a most interesting therapeutic possibility. Perhaps the major potential problem is that A_2A receptors also appear to have important effects on platelets and inflammatory cells.

Pain

It has been known by physicians and the public for several centuries that caffeine alleviates certain types of pain and aggravates other types. The receptors responsible for these effects are still poorly known.⁵³ What is clear is that there are A₁ receptors in the spinal cord and that they mediate antinociception.²³ Clearly, inhibition of these receptors would cause enhanced, rather than reduced, sensitivity to pain. However, these A₁ receptors may be a target for development of therapeutic agonists. Indeed, intrathecal adenosine in humans has indicated significant pain relief with few side effects.⁵⁴ Interestingly, systemic adenosine re-duces several types of pain in hu-mans.^55,56 Again, the mechanisms involved are poorly understood.

Adenosine A_2A receptors appear to be involved in enhancing nociception via a peripheral site of action.²⁸ In addition, A_2A receptors increase blood flow.⁵⁷ Antagonism of either of these effects might explain the ability of caffeine to reduce headache. In addition, A_2B receptor-mediated effects on cerebral blood flow could be involved. Finally, the ability of A₃ receptors to enhance inflammatory reactions could indicate that blockade of these receptors might be beneficial in some types of pain.

Epilepsy

It has long been known that adenosine, presumably acting on A₁ receptors, can decrease seizure-like neuronal activity in vitro^58,59 and in vivo,⁶⁰ and that adenosine is released upon such activity in vitro^59,61 and in vivo.⁶² Since adenosine receptor antagonists can, moreover, increase seizure-like activity in vitro⁶³ and in vivo,⁶⁴ adenosine can be considered an endogenous antiepileptic agent. Therapies designed to bolster its activity may be an interesting approach. However, there are rapid adaptive changes, and protective effects of agonists may be converted to seizure promotion. Conversely, long-term use of antagonists may be protective.⁶⁵

Kidney

Caffeine is known to increase urine production and sodium excretion. These effects appear due to blockade of A₁ receptors. In addition A₁ receptors are critically involved in mediating tubuloglomerular feedback.²⁵ The effect of A₁ receptor stimulation on glomerular filtration appears to depend on the renin-angiotensin system.⁶⁶ Indeed, antagonists at A₁ receptors have been tried in kidney disease.⁶⁷ Their use may be particularly interesting in chronic renal failure. However, the A_2A receptor is also a target for therapy in kidney disease.⁶⁸ In this case agonists are interesting because they can decrease inflammatory reactions.

Metabolism

There is considerable evidence that adenosine, acting on A₁ receptors, can potently reduce lipid metabolism and that alterations in A₁ receptors may occur in obesity.⁶⁹ In addition, adenosine can interact with the effects of insulin in target tissues including adipose tissue, skeletal muscle and the heart.⁷⁰ The results are not always clear-cut and the receptors involved not fully characterized. Nevertheless, drugs acting on adenosine receptors might prove useful in, for example, type 2 diabetes and the so-called metabolic syndrome.

Hypoxia/ischemia

It has long been known that adenosine plays a particularly important role in hypoxia or ischemia. Thus, adenosine is a key mediator of vasodilatation in several vascular beds, and several different receptors appear to be invol-ved.^57,71 Furthermore, the actions of adenosine also have long-term effects, including release of VEGF to cause increased numbers of blood vessels.⁷¹ There is abundant evidence that adenosine is an endogenous neuroprotective and cardioprotective agent. Most of the receptors have been implicated. Given that levels of adenosine rise markedly under these conditions (see above), there may not be much scope for additional effects via receptor agonism. It is, however, intriguing that blockade of A_2A receptors has repeatedly been shown to offer protection.³⁰ This may offer a more reasonable therapeutic strategy.

Preconditioning

Another possibility is offered by the probable role of adenosine as a key player in preconditioning. Adenosine receptors are one of the most attrac- tive targets in ischemic preconditioning,^72-75 and adenosine derivatives can mimic not only the early, but the late phase of preconditioning.⁷⁶ It has also been suggested that drugs that act on adenosine receptors could be beneficial in alleviating symptoms of ischemia in extremities, perhaps partly via preconditioning mechanisms.⁷⁷ The interesting aspect is that an agonist may be used transiently to precondition the heart or other tissues.

Asthma

Caffeine and its metabolite theophylline have long been known to be antiasthmatic. As noted above, an antisense experiment implicated adenosine A₁ receptors, but most evidence focuses on A₃ or A_2B receptors.⁴⁰ Possibly, the fact that a theophylline relative, enprofylline, is more effective than theophylline as an antiasthmatic and yet is only active against adenosine A_2B receptors⁷⁸ could mean that these receptors are particularly important. Although most efforts to develop antiasthmatic therapy have examined antagonists, another possibility could be to use A_2A agonists, because they have a broad antiinflammatory acti-vity.⁷⁹

Conclusion

The above brief summary has indicated a few possibilities for adenosine receptor-based therapy. Obviously, much more could be said, and more therapeutic areas exist. The interested reader is therefore strongly urged to peruse some of the more extensive reviews referred to in this minireview.

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Bertil B. Fredholm is Professor in the Department of Physiology and Phar-macology, Karolinska Institutet, S-17177 Stockholm, Sweden; Fax: + 46-8-7287939; E-mail: bertil.fredholm@fyfa.ki.se.

Drug News & Perspectives Vol. 16, No. 5, 2003, p. 283-289
ISSN 0214-0934 Copyright 2003 Prous Science, S.A. CCC: 0214 0934/2003 http://www.prous.com

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