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Structural determinants of affinity of N(6)-substituted-5'-C-(ethyltetrazol-2-yl)adenosine and 2-chloroadenosine derivatives at adenosine receptor (AR) subtypes were studied with binding and molecular modeling. Small N(6)-cycloalkyl and 3-halobenzyl groups furnished potent dual acting A1AR agonists and A3AR antagonists. 4 was the most potent dual acting human (h) A1AR agonist (Ki = 0.45 nM) and A3AR antagonist (Ki = 0.31 nM) and highly selective versus A2A; 11 and 26 were most potent at both h and rat (r) A3AR. All N(6)-substituted-5'-C-(ethyltetrazol-2-yl)adenosine derivatives proved to be antagonists at hA3AR but agonists at the rA3AR. Analgesia of 11, 22, and 26 was evaluated in the mouse formalin test (A3AR antagonist blocked and A3AR agonist strongly potentiated). N(6)-Methyl-5'-C-(ethyltetrazol-2-yl)adenosine (22) was most potent, inhibiting both phases, as observed combining A1AR and A3AR agonists. This study demonstrated for the first time the advantages of a single molecule activating two AR pathways both leading to benefit in this acute pain model.

Objective : To investigate the effects of the interaction between adenosine receptors and renal nerves on renin release. Materials and methods : The effects on renin secretion of A 1 (2-chloro-N6-cyclopentil-adenosine) and A 2 (2-hexynil-5'-N-ethyl-carboxamido-adenosine) adenosine-receptor agonists were studied in two groups of anaesthetized rats, each with one kidney surgically denervated. Arterial blood pressure and the renal blood flow of innervated and denervated kidneys were continuously recorded. Cannulae were inserted into both renal veins through femoral veins. After 1 h of rest, A 1 and A 2 agonists were intravenously infused for 30 min in the two groups of rats. Plasma renin activity was measured by radioimmunoassay in blood samples drawn simultaneously from both renal veins and the femoral artery before and after the drug infusion. Results : Infusions of A 1 and A 2 agonists produced comparable hypotensive effects. During A 1 agonist administration, the heart rate decreased significantly, but it did not change after A 2 agonist treatment. Renal blood flow was reduced by administration of the A 1 agonist in both kidneys, while A 2 agonist administration significantly reduced the renal blood flow of the innervated kidney only. The veno-arterial difference in plasma renin activity decreased after the A 1 agonist infusion in both kidneys, but after the A 2 agonist infusion it increased significantly in the innervated kidney only. Conclusions : Renal nerves do not influence the inhibition of renin release mediated by A 1 adenosine receptors. In vivo, A 2 -receptor agonist administration can stimulate renin release only in the presence of intact renal nerves.