8-Polycycloalkyl-1,3-dipropylxanthines as potent and selective antagonists for A1-adenosine receptors.
With the aim of characterizing the hydrophobic interactions between xanthines and the A1 receptor site, 1,3-dipropyl-8-substituted xanthines were synthesized. Introduction of a quaternary carbon and the conformationally restricted cyclopentyl moiety into the 8-position of xanthines enhanced the adenosine A1 antagonism. 1,3-Dipropyl-8-(3-noradamantyl)xanthine was identified to be a selective and the most potent A1 receptor antagonist reported to date. Under our structure-activity relationship, the 8-substituent of xanthine antagonists and the N6-substituent of adenosine agonists appears to bind to the same region of the A1 receptor.
Shimada
J
J
Pharmaceutical Research Laboratories, Kyowa Hakko Kogyo Co., Ltd., Shizuoka-ken, Japan.
Suzuki
F
F
Nonaka
H
H
Ishii
A
A
D000241:Adenosine / Q000031:analogs & derivatives / Q000378:metabolism; D019830:Adenosine-5'-(N-ethylcarboxamide); D000818:Animals; D001667:Binding, Competitive; D002462:Cell Membrane / Q000378:metabolism; D003342:Corpus Striatum / Q000378:metabolism; D006168:Guinea Pigs; D006801:Humans; D008968:Molecular Conformation; D015394:Molecular Structure; D016548:Prosencephalon / Q000378:metabolism; D058914:Purinergic Antagonists; D051381:Rats; D011983:Receptors, Purinergic / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014970:Xanthines / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology
D058914:Purinergic Antagonists; D011983:Receptors, Purinergic; D014970:Xanthines; D019830:Adenosine-5'-(N-ethylcarboxamide); C027513:N(6)-cyclohexyladenosine; C073525:rolofylline; D000241:Adenosine