Synthesis of hybrid analogues of caffeine and eudistomin D and its affinity for adenosine receptors.
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 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. 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 beta-position of the pyridine ring (beta-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 delta-position of the pyridine ring (delta-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 microM).
Ishiyama
Haruaki
H
Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
Nakajima
Hikaru
H
Nakata
Hiroyasu
H
Kobayashi
Jun'ichi
J
D001667:Binding, Competitive; 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; D011485:Protein Binding; D018047:Receptors, Purinergic P1 / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship
D002243:Carbolines; D008024:Ligands; D018047:Receptors, Purinergic P1; D011994:Recombinant Proteins; C520303:eudistomin D; D002110:Caffeine