New potent and selective A 1 adenosine receptor antagonists as potential tools for the treatment of gastrointestinal diseases.

The synthesis of 9-alkyl substituted adenine derivatives presenting aromatic groups and cycloalkyl rings in 8- and N ⁶ -position, respectively, is reported. The compounds were tested with radioligand binding studies showing, in some cases, a low nanomolar A ₁ adenosine receptor affinity and a very good selectivity versus the other adenosine receptor subtypes. Functional assays at human adenosine receptors and at a mouse ileum tissue preparation clearly demonstrate the antagonist profile of these molecules, with inhibitory potency at nanomolar level. A molecular modeling study, consisting in docking analysis at the recently reported A ₁ adenosine receptor crystal structure, was performed for the interpretation of the obtained pharmacological results. The N ⁶ -cyclopentyl-9-methyl-8-phenyladenine (17), resulting the most active derivative of the series (K _i  = 2.8 nM and IC ₅₀  = 14 nM), was also very efficacious in counteracting the effect of the agonist CCPA on mouse ileum contractility. This new compound represents a tool for the development of new agents for the treatment of intestinal diseases as constipation and postoperative ileus.
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