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 beta-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. 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 delta-position of the pyridine ring (delta-N type) showed the most potent affinity for adenosine receptor A(3) 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 beta-position of the pyridine ring (beta-N type) showed lower affinity than the corresponding delta-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.
Ohshita
Kengo
K
Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan.
Ishiyama
Haruaki
H
Oyanagi
Koshi
K
Nakata
Hiroyasu
H
Kobayashi
Jun'ichi
J
D001665:Binding Sites; D002110:Caffeine / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000494:pharmacology*; D002243:Carbolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D006801:Humans; D008024:Ligands; D015394:Molecular Structure; D018047:Receptors, Purinergic P1 / Q000187:drug effects*; D013329:Structure-Activity Relationship
D002243:Carbolines; D008024:Ligands; D018047:Receptors, Purinergic P1; C520303:eudistomin D; D002110:Caffeine