N6-substituted adenosine receptor agonists. Synthesis and pharmacological activity as potent antinociceptive agents.

Novel N-6-(indol-3-yl)alkyl derivatives of adenosine were synthesized. The adenosine receptor affinity and the antinociceptive activity of these compounds were assessed in binding studies and the phenylbenzoquinone-induced writhing test. Most of these analogues exhibited a potent analgesic activity without side effects. Among them, compound 3c (UP 202-32) bound to A(1) (K-i = 110 nM) and A(2) (K-i = 350 nM) adenosine receptors in a specific manner since it did not interact with many other receptors,especially opioid binding sites. The antinociceptive activity in the phenylbenzoquinone assay (ED(50) = 3.3 mg/kg po) was antagonized by 8-cyclopentyl-theophylline, suggesting that an adenosinergic mechanism underlies the analgesic activity observed with this compound. The data obtained with these new N-6-substituted adenosine receptor agonists emphasize the interest of such compounds in the treatment of pain.