Defibrotide, a single-stranded polydeoxyribonucleotide acting as an adenosine receptor agonist.
The binding of single-stranded polydeoxyribonucleotides to adenosine A1 and A2 receptors was investigated. Defibrotide, a natural substance with established anti-thrombotic and anti-ischaemic effects, displaced [3H]CHA (N6-cyclohexyl-adenosine) and [3H]NECA (5'-N-ethylcarboxamido-adenosine) concentration dependently, completely and competitively. Ki values of 371 +/- 68 and 688 +/- 115 micrograms/ml (mean +/- S.E.M. of 4-5 replications) were computed for adenosine A1 and A2 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 (IC50 = 4001 micrograms/ml) about one-third as potently as the CHA-contracted preparation and as potently as the resting preparation. NECA, a mixed adenosine A1/A2 receptor agonist, behaved similarly. The effects were abolished by the adenosine A1/A2 receptor blocker 8-phenyltheophylline, but not by the selective A1 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.
Bianchi
G
G
Biological Research Lab., Crinos Industria Farmacobiologica S.p.A., Como, Italy.
Barone
D
D
Lanzarotti
E
E
Tettamanti
R
R
Porta
R
R
Moltrasio
D
D
Cedro
A
A
Salvetti
L
L
Mantovani
M
M
Prino
G
G
D000241:Adenosine / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D019830:Adenosine-5'-(N-ethylcarboxamide); D000818:Animals; D001667:Binding, Competitive; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D005343:Fibrinolytic Agents / Q000378:metabolism / Q000494:pharmacology*; D006168:Guinea Pigs; D008297:Male; D011089:Polydeoxyribonucleotides / Q000378:metabolism / Q000494:pharmacology*; D058915:Purinergic P1 Receptor Antagonists; D011869:Radioligand Assay; D051381:Rats; D018047:Receptors, Purinergic P1 / Q000187:drug effects* / Q000378:metabolism; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism
D005343:Fibrinolytic Agents; D011089:Polydeoxyribonucleotides; D058915:Purinergic P1 Receptor Antagonists; D018047:Receptors, Purinergic P1; D019830:Adenosine-5'-(N-ethylcarboxamide); C027513:N(6)-cyclohexyladenosine; C036901:defibrotide; D000241:Adenosine