Elsevier

Drug Discovery Today

Volume 4, Issue 12, 1 December 1999, Pages 542-551
Drug Discovery Today

Review
Adenosine receptors as potential therapeutic targets

https://doi.org/10.1016/S1359-6446(99)01421-XGet rights and content

Abstract

Recent studies indicate a widening role for adenosine receptors in many therapeutic areas. Adenosine receptors are involved in immunological and inflammatory responses, respiratory regulation, the cardiovascular system, the kidney, various CNS-mediated events including sleep and neuroprotection, as well as central and peripheral pain processes. In this review, the physiological role of adenosine receptors in these key areas is described with reference to the therapeutic potential of adenosine receptor agonists and antagonists.

Section snippets

Inflammatory and immunological responses

Adenosine receptors play a modulatory role in inflammatory responses and there is increasing evidence for use of adenosine and its analogues in the treatment of severe inflammatory diseases such as arthritis5, 6 and asthma7, 8, 9, as well as for more general inflammatory processes such as wound healing10.

Cardiovascular system

Adenosine is effective as an antiarrhythmic agent in the treatment of tachycardia, or for unmasking atrial tachyarrhythmias or ventricular pre-excitation. By slowing down the electrical conductance in the sinus and atrioventricular nodes, adenosine slows down or terminates abnormal cardiac rhythms25, 26, 27. Because of the short half-life of adenosine, potentially serious side effects, such as atrial or ventricular fibrillation, apnea and acceleration of ventricular tachycardia, are usually

Renal system

Adenosine receptors are widely distributed throughout the nephron, mediating several effects in the renal system, therefore reducing the risk of cardiovascular disease in hypertensive patients45. Inhibition of adenosine deaminase has been shown to lower blood pressure in older but not younger spontaneous hypertensive rats. Hence, cardiovascular protection in older hypertensive patients might be achieved by using adenosine deaminase inhibitors45. Meanwhile, blockade of renal adenosine receptors

Parkinson’s disease

Several studies have recently suggested that the A2-receptor subtype is physiologically relevant in cerebral ischaemia54, neurological disorders55, 56 and neurodegenerative processes such as Parkinson’s disease54, 57, 58, 59.

The modulatory role of adenosine on dopamine and N-methyl-d-aspartate (NMDA)-receptor neurotransmission indicates a possible therapeutic potential for adenosine receptors in CNS disorders such as schizophrenia, dementia and depression (Fig. 3). Human studies with

Pain

Adenosine influences pain transmission both centrally and peripherally. In an inflammatory model of thermal hyperalgesia, spinally administered adenosine receptor agonists produce antinociception through the activation of A1 receptors74. The A1- and A2-receptor agonists, N6-cyclohexyladenosine (CHA) and CGS21680, and the adenosine kinase inhibitors, 5′-amino-5′deoxyadenosine (NH2dADO) and 5-iodotubercidin (ITU), produced antinociception in unilateral hind paw carrageenan-induced thermal

Conclusions

Adenosine receptors are widely distributed throughout the body. Recent studies demonstrate that adenosine receptors are involved in complex regulatory systems. A clear understanding of the specific interactions in the cardiovascular, respiratory, renal, central and peripheral nervous systems and in immunological and inflammatory processes are likely to lead to new approaches for the use of adenosine receptor agonists and antagonists in a wide range of diseases.

References (93)

  • I. Feoktistov

    Trends Pharmacol. Sci.

    (1998)
  • J. Linden

    Life Sci.

    (1998)
  • Y. Kohno

    Blood

    (1996)
  • K.D. Nantwi et al.

    Neuropharmacology

    (1998)
  • S.L. Wilbur et al.

    Am. J. Cardiol.

    (1997)
  • B.D. Bertolet

    J. Am. Coll. Cardiol.

    (1996)
  • J.C. Shryock et al.

    Am. J. Cardiol.

    (1997)
  • U. Elkayam

    J. Am. Coll. Cardiol.

    (1998)
  • B.H. Tian

    Exp. Eye Res.

    (1997)
  • P. Popoli et al.

    Eur. J. Pharmacol.

    (1997)
  • S.H. Kafka et al.

    Eur. J. Pharmacol.

    (1996)
  • S.N. Mandhane et al.

    Eur. J. Pharmacol.

    (1997)
  • M.R. Zarrindast

    Eur. J. Pharmacol.

    (1997)
  • P.J. GebickeHaerter

    Neurochem. Int.

    (1996)
  • D.G. MacGregor

    Brain Res.

    (1996)
  • P.A. Jones et al.

    Brain Res.

    (1998)
  • D.K.J.E. VonLubitz

    Eur. J. Pharmacol.

    (1996)
  • C.M. Fraser

    Eur. Neuropsychopharmacol.

    (1997)
  • C.M. Fraser

    Eur. Neuropsychopharmacol.

    (1996)
  • S. Satoh et al.

    Eur. J. Pharmacol.

    (1998)
  • J.P. Huston

    Neuroscience

    (1996)
  • A. Poon et al.

    Pain

    (1998)
  • J. Sawynok

    Eur. J. Pharmacol.

    (1998)
  • J. Sawynok et al.

    Pain

    (1998)
  • J. Sawynok

    Eur. J. Pharmacol.

    (1997)
  • J.G. Cui

    Neurosci. Lett.

    (1998)
  • J.G. Cui

    Neurosci. Lett.

    (1997)
  • K.F. Sjolund

    Neurosci. Lett.

    (1998)
  • T. Sumida

    Pain

    (1998)
  • G.B. Kaplan et al.

    Brain Res.

    (1997)
  • H.W. Suh et al.

    Neuropeptides

    (1997)
  • R.J. Hill

    J. Mol. Cell. Cardiol.

    (1998)
  • M.E. Olah et al.

    Annu. Rev. Pharmacol. Toxicol.

    (1995)
  • L. Birnbaumer et al.

    J. Recept. Signal Transduct. Res.

    (1995)
  • S-A. Poulsen et al.

    Bioorg. Med. Chem.

    (1998)
  • C.E. Muller et al.

    Curr. Pharm. Design

    (1996)
  • C. Szabo

    Br. J. Pharmacol.

    (1998)
  • B.N. Cronstein et al.

    Drug Dev. Res.

    (1996)
  • J.A. Auchampach

    Mol. Pharmacol.

    (1997)
  • M.C. Montesinos

    J. Exp. Med.

    (1997)
  • G. Haskó

    J. Immunol.

    (1996)
  • F.G. Sajjadi

    J. Immunol.

    (1996)
  • B.B. Fredholm et al.

    Naunyn-Schmiedeberg’s Arch. Pharmacol.

    (1996)
  • M.G. Bouma et al.

    Am. J. Physiol. Cell Physiol.

    (1996)
  • K. Varani

    Br. J. Pharmacol.

    (1997)
  • J.W. Nyce et al.

    Nature

    (1997)
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