Recent Progress in the Development of Adenosine Receptor Ligands as Antiinflammatory Drugs
Rhalid Akkari, Joachim C. Burbiel, Jorg Hockemeyer and Christa E. Muller
Affiliation: Universitat Bonn,Pharmazeutisches Institut, Pharmazeutische Chemie Poppelsdorf,Kreuzbergweg 26, 53115 Bonn.
Keywords: Xanthine antagonist, Pyridazinone derivatives, pyrazine derivatives, inflammation, MRE-0094, Asthma
Adenosine receptors belong to the family of G protein-coupled receptors. Four distinct subtypes are known, termed A1, A2A, A2B and A3. Adenosine is an important signaling molecule which is released under inflammatory conditions. It can show antiinflammatory as well as proinflammatory activities, and the contribution of the specific adenosine receptor subtypes in various cells, tissues and organs is complex. Agonists selective for adenosine A1 receptors show antinociceptive activity and are active in animal models of neuropathic and inflammatory pain. Adenosine A2A receptor agonists are potent antiinflammatory drugs. A2A-selective antagonists have shown antihyperalgesic activity in animal models of inflammatory pain. For A2B agonists as well as A2B antagonists antiinflammatory activity has been postulated. Selective A2B antagonists were shown to decrease (inflammatory) pain, and are promising candidates for the treatment of asthma. Adenosine A3 receptor agonists appear to be proinflammatory, while there is evidence for an antiinflammatory effect of A3 antagonists. There are some contradictory findings, and A 3 agonists are being developed for the treatment of inflammatory diseases such as arthritis. Indirect mechanisms increasing the extracellular concentration of adenosine using adenosine kinase inhibitors, adenosine deaminase inhibitors or adenosine uptake inhibitors, or increasing the potency of adenosine at the A1 receptor subtype by allosteric modulators lead to potent antinociceptive and antiinflammatory activity. The advantage of indirectly acting drugs may be their site- and event-specific action since they are only active where adenosine has been released. In the past decade considerable progress has been made towards the identification of novel lead structures and the development of potent and selective ligands for all four adenosine receptor subtypes. A large number of patents has recently been filed and the field is finally in the process of translating many years of basic science into therapeutic application. This review article will focus on compounds published or patented within the past three years.
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