Defibrotide, a single-stranded polydeoxyribonucleotide acting as an adenosine receptor agonist.

Abstract The binding of single-stranded polydeoxyribonucleotides to adenosine A 1 and A 2 receptors was investigated. Defibrotide, a natural substance with established anti-thrombotic and anti-ischaemic effects, displaced [ 3 H]CHA (N 6 -cyclohexyl-adenosine) and [ 3 H]NECA (5′-N-ethylcarboxamido-adenosine) concentration dependently, completely and competitively. K i values of 371±68 and 688±115 μ g/ml (mean±S.E.M. of 4–5 replications) were computed for adenosine A 1 and A 2 sites, respectively. Higher and lower molecular weight polydeoxyribonucleotides displayed comparable affinity, whereas a double-stranded polydeoxyribonucleotide and a polyanion with a negative charge comparable to that of defibrotide were inactive. Defibrotide did not affect the total number of binding sites in radioligand saturation experiments. Defibrotide relaxed the K + -contracted guinea-pig trachealis muscle (IC 50 = 4001 μg/ml) about one-third as potently as the CHA-contracted preparation and as potently as the resting preparation. NECA, a mixed adenosine A 1 /A 2 receptor agonist, behaved similarly. The effects were abolished by the adenosine A 1 /A 2 receptor blocker 8-phenyltheophylline, but not by the selective A 1 blocker, 1,3-dipropyl-8-(2-amino-4-chlorophenyl)- xanthine. These results demonstrate that defibrotide binds to adenosine receptors and triggers pharmacological responses comparable to those of a known agonist.