Synthesis of hybrid molecules of caffeine and eudistomin D and its effects on adenosine receptors

Four hybrid molecules (1 and 12-14) of caffeine and eudistomin D, a β-carboline alkaloid from a marine tunicate, were synthesized, and their affinity and selectivity for adenosine receptors A1, A2A, and A3 were examined. It was found that all the compounds showed better potency as adenosine receptor ligands as compared with caffeine. Among them, a compound (13) possessing a nitrogen at the δ-position of the pyridine ring (δ-N type) showed the most potent affinity for adenosine receptor A3 subtype, while N-methylation (14) of a pyrrole ring in 13 significantly lowered the potency as adenosine receptor ligands. Compounds (1 and 12) having a nitrogen at the β-position of the pyridine ring (β-N type) showed lower affinity than the corresponding δ-N type compounds (13 and 14), while compounds (10, 11, and 17) lacking a pyrrole ring between the pyridine and pyrimidine rings exhibited almost no affinity to the adenosine receptor subtypes examined.