Synthesis of hybrid analogues of caffeine and eudistomin D and its affinity for adenosine receptors

Abstract

Four bis- N- n-propyl analogues ( 3– 6) in the uracil ring of two hybrid molecules ( 1 and 2) of caffeine and eudistomin D, a β-carboline alkaloid from a marine tunicate, were synthesized, and their affinity and selectivity for adenosine receptors A 1, A 2A, and A 3 were examined. All the compounds ( 3– 6) showed better potency as adenosine receptor ligands than caffeine. Bis- N- n-propylation ( 3 and 4, respectively) of the uracil ring in 1 and 2 resulted in higher affinity for A 1 and A 2A adenosine receptors. Furthermore, it was found that a compound ( 5) possessing a n-propyloxy group at C-7 in compound 3 with a nitrogen at the β-position of the pyridine ring (β- N type) enhanced remarkably affinity for adenosine receptor A 3 subtype, while n-propyloxy substitution (compound 6) at C-5 in compound 4 with a nitrogen at the δ-position of the pyridine ring (δ- N type) reduced affinity for all the adenosine receptor, A 1, A 2A, and A 3. Among all the compounds ( 1– 6) examined, compound 5 showed the most potent affinity for adenosine receptor A 3 subtype ( K i value, 0.00382 μM).