Pharmacologic characterization of novel adenosine A2A receptor agonists in equine neutrophils

Wan Chun Sun, James N. Moore, David J. Hurley, Michel L. Vandenplas, Joel M. Linden, Thomas F. Murray

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Abstract

Objective - To evaluate anti-inflammatory effects of several novel adenosine receptor agonists and to determine their specificity for various adenosine receptor subtypes on neutrophils, cells heterologously expressing equine adenosine receptors, or equine brain membranes. Sample Population - Neutrophils isolated from 8 healthy horses. Procedures - Radioligand binding experiments were performed to compare binding affinities of adenosine receptor agonists to equine adenosine A1, A2A, and A3 receptor subtypes. Effects of these agonists on endotoxin-induced production of reactive oxygen species (ROS) by equine neutrophils and roles of specific adenosine receptor subtypes and cAMP production in mediating these effects were determined. Results - Radioligand binding experiments yielded a ranked order of affinity for the brain equine A2A receptor on the basis of 50% inhibitory concentrations (IC50) of the agonists as follows: ATL307 (IC50 = 1.9nM) and ATL313 > ATL309 and ATL310 > ATL202 > 2-([p-2-carboxyethyl] phenylethylamino)- 5′-N-ethylcarboxyamidoadenosine > 5′- N-ethylcarboxamidoadenosine. Furthermore, ATL313 had approximately 100-fold greater selectivity for A2A over A1 and A3 receptors. In functional assays with equine neutrophils, the compounds inhibited endotoxin-induced ROS production and stimulated production of cAMP with the same ranked order of potency. Results of experiments performed with selective adenosine receptor antagonists indicated that functional effects of ATL313 were via stimulation of A2A receptors. Conclusions and Clinical Relevance - Results indicated that activation of A2A receptors exerted anti-inflammatory effects on equine neutrophils and that stable, highly selective adenosine A2A receptor agonists may be developed for use in management of horses and other domestic animals with septic and nonseptic inflammatory diseases.

Original languageEnglish (US)
Pages (from-to)981-987
Number of pages7
JournalAmerican Journal of Veterinary Research
Volume68
Issue number9
DOIs
StatePublished - Sep 1 2007

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All Science Journal Classification (ASJC) codes

  • veterinary(all)

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