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Eur J Pharmacol. 2004 Oct 6;501(1-3):79-86.

Involvement of adenosine A1 receptors in upregulation of nitric oxide by acyclic nucleotide analogues.

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Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Vídenská 1083, 142 20 Prague 4, Czech Republic.


Acyclic nucleoside phosphonates are a novel class of virostatics effective against replication of both DNA-viruses and retroviruses. They are synthetic analogues of natural nucleotide monophosphates, and purine derivatives thus represent counterparts of AMP. Mono- and di-phosphorylated species are analogues of natural ADP and ATP, respectively. A number of these compounds are endowed with immunostimulatory and immunomodulatory potential. We investigated whether their augmenting effect on the interferon-gamma-primed production of nitric oxide (NO) by murine macrophages is mediated by purinoceptors. The test compounds comprise alterations at the N(6)-group of the heterocyclic base, i.e., adenine or 2,6-diaminopurine, and at the N(9)-side chain, represented by 9-[2-(phosphonomethoxy)ethyl] and 9-[2-(phosphonomethoxy)propyl] moieties: 9-[2-(phosphonomethoxy)propyl]adenine [(R)-PMPA; tenofovir], N(6)-cyclopropyl-(R)-9-[2-(phosphonomethoxy)propyl]2,6-diaminopurine [N(6)-cyclopropyl-(R)-PMPDAP], N(6)-cyclopentyl-(R)-9-[2-(phosphonomethoxy)propyl]2,6-diaminopurine [N(6)-cyclopentyl-(R)-PMPDAP], N(6)-dimethylaminoethyl-(R)-9-[2-(phosphonomethoxy)propyl]2,6-diaminopurine [N(6)-dimethylaminoethyl-(R)-PMPDAP], N(6)-isobutyl-9-[2-(phosphonomethoxy)ethyl]2,6-diaminopurine (N(6)-isobutyl-PMEDAP), N(6)-cyclopentyl-9-[2-(phosphonomethoxy)ethyl]2,6-diaminopurine (N(6)-cyclopentyl-PMEDAP), N(6)-cyclooctyl-9-[2-(phosphonomethoxy)ethyl]2,6-diaminopurine (N(6)-cyclooctyl-PMEDAP), and N(6)-cyclohexylmethyl-9-[2-(phosphonomethoxy)ethyl]2,6-diaminopurine (N(6)-cyclohexylmethyl-PMEDAP). The cells were cultured in the presence of interferon-gamma (5000 pg/ml) and test compounds (2-50 microM). Formation of nitrites was determined after 24 h using Griess reagent. It was inhibited by specific and nonspecific antagonists of adenosine A(1) receptors (IC(50) for 8-cyclopentyl-1,3-dipropylxanthine [CPX] was approximately 10 microM), while all other purine P(1) and purine P(2) receptor antagonists remained ineffective to suppress the NO-synergistic effect of acyclic nucleoside phosphonates.

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