Adenosine A 2A receptor agonists may be important regulators of inflammation. Such conclusions have come from studies demonstrating that, (i) adenosine A 2A agonists exhibit anti-inflammatory properties in vitro and in vivo, (ii) selective A 2A antagonists enhance inflammation in vivo and, (iii) knock outs of this receptor aggravate inflammation in a wide variety of in vivo models. Inflammation is a hallmark of asthma and COPD and adenosine has long been suggested to be involved in disease pathology. Two recent publications, however, suggested that an inhaled adenosine A 2A receptor agonist (GW328267X) did not affect either the early and late asthmatic response or symptoms associated with allergic rhinitis suggesting that the rationale for treating inflammation with an adenosine A 2A receptor agonist may be incorrect. A barrier to fully investigating the role of adenosine A 2A receptor agonists as anti-inflammatory agents in the lung is the side effect profile due to systemic exposure, even with inhalation. Unless strategies can be evolved to limit the systemic exposure of inhaled adenosine A 2A receptor agonists, the promise of treating lung inflammation with such agents may never be fully explored. Using strategies similar to that devised to improve the therapeutic index of inhaled corticosteroids, UK371,104 was identified as a selective agonist of the adenosine A 2A receptor that has a lung focus of pharmacological activity following delivery to the lung in a pre clinical in vivo model of lung function. Lung-focussed agents such as UK371,104 may be suitable for assessing the anti-inflammatory potential of inhaled adenosine A 2A receptor agonists.
The broad spectrum anti-inflammatory actions of adenosine A(2A) receptor agonists are well described. The wide distribution of this receptor, however, suggests that the therapeutic potential of these agents is likely to reside in topical treatments to avoid systemic side effects associated with oral administration. Adenosine A(2A) receptor agonists have been assessed as topical agents: GW328267X (GSK; allergic rhinitis and asthma), UK-432097 (Pfizer; chronic obstructive pulmonary disease [COPD]) and Sonedenoson (MRE0094, King Pharmaceuticals; wound healing). All trials failed to achieve effects against the desired clinical end points. This broad-based review will discuss general principles of chemical design of topically applied agents and potential therapeutic topical applications of current adenosine A(2A) receptor agonists. Potential factors contributing to the lack of efficacy in the above clinical trials will be discussed together with design principles, which may influence efficacy in disease states. Our analysis suggests that adenosine A(2A) receptor agonists have a wide therapeutic potential as topical agents in a wide variety of diseases, such as neutrophil-dependent lung diseases (acute lung injury, exacerbations in asthma and COPD), allergic rhinitis, glaucoma and wound repair. Factors that will influence topical activity include formulation, tissue retention, compound potency, receptor kinetics and pharmacokinetics.
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