8-Aryl-and 8-cycloalkyl-1,3-dipropylxanthines: further potent and selective antagonists for A1-adenosine receptors.
A series of 1,3-dipropylxanthines were prepared with a variety of substituents at the 8-position. These included 8-aryl and 8-cycloalkyl groups. Polar carboxylate and carboxamide moieties were introduced as aryl substituents to increase water solubility. 1,3-Dipropyl-8-[2-hydroxy-4-[(carboxymethyl)oxy]phenyl]xanthine provided a functionalized congener with high potency (Ki = 37 nM) and selectivity (54-fold) for A1-adenosine receptors. This congener was used for preparation of a series of other analogues, some with higher potency and some with higher selectivity. 8-Cyclopentyl- and 8-cyclohexyl-1,3-dipropylxanthines were both very potent (Ki = 1-1.5 nM) and selective for A1 receptors, while 8-cycloalkylmethyl analogues were 10-fold less potent, but still very selective for A1 receptors. 8-Piperidinyl and 8-pyrazinyl analogues had very low activities as adenosine receptor antagonists.
Shamim
M T
MT
Laboratory of Bioorganic Chemistry, National Institute of Diabetes, Digestive and Kidney Diseases, Bethesda, Maryland 20892.
Ukena
D
D
Padgett
W L
WL
Hong
O
O
Daly
J W
JW
D000067956:Adenylyl Cyclase Inhibitors; D000818:Animals; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D010660:Phenylisopropyladenosine / Q000378:metabolism; D051381:Rats; D011983:Receptors, Purinergic / Q000187:drug effects* / Q000378:metabolism; D012995:Solubility; D013329:Structure-Activity Relationship; D014970:Xanthines / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology
D000067956:Adenylyl Cyclase Inhibitors; D011983:Receptors, Purinergic; D014970:Xanthines; D010660:Phenylisopropyladenosine