Adenosine A1 antagonists. 2. Structure-activity relationships on diuretic activities and protective effects against acute renal failure.
Diuretic activities of xanthine or nonxanthine adenosine antagonists and their ameliorative effects against glycerol-induced acute renal failure in rats were investigated in order to clarify the physiological and pathological function of adenosine receptors in the kidney. Diuretic and natriuretic activities of a variety of adenosine antagonists clarified systematically for the first time that the blockade of A1 receptors is more important than that of A2 receptors in sodium and water excretion and support the hypothesis that endogenous intrarenal levels of adenosine directly enhance tubular sodium readsorption. Studies of structure-activity relationships of 8-substituted xanthines in the acute renal failure demonstrated that the activation of adenosine A1 receptor was an important factor in developing such a renal failure. A series of 8-(3-noradamantyl)xanthines exhibited the extremely potent diuretic and natriuretic activities (24; 2.5 micrograms/kg, po, the ratio of urinary excretion value in treated rats to urinary excretion value in control rats = 1.69, the ratio of Na+/K+ in treated rats to Na+/K+ in control rats = 1.76) and potent ameliorative effects against glycerol-induced acute renal failure (24; 10 micrograms/kg, ip, 55% inhibition). From our detailed studies of structure-activity relationships, we can speculate that some tissue differences of the adenosine A1 receptor might exist between kidney and brain and sites of action for adenosine antagonists could be different between two renal pharmacological assays. 1,3-Dipropyl-8-(3-noradamantyl)xanthine, KW-3902 (24), was chosen for further studies and is under development as a drug for treating the acute renal failure.
Suzuki
F
F
Pharmaceutical Research Laboratories, Kyowa Hakko Kogyo Co., Ltd., Shizuoka-ken, Japan.
Shimada
J
J
Mizumoto
H
H
Karasawa
A
A
Kubo
K
K
Nonaka
H
H
Ishii
A
A
Kawakita
T
T
D058186:Acute Kidney Injury / Q000517:prevention & control*; D000241:Adenosine / Q000037:antagonists & inhibitors*; D000818:Animals; D002414:Cations, Monovalent; D004232:Diuretics / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D011188:Potassium / Q000652:urine; D011869:Radioligand Assay; D051381:Rats; D011919:Rats, Inbred Strains; D011983:Receptors, Purinergic / Q000378:metabolism; D012964:Sodium / Q000652:urine; D013329:Structure-Activity Relationship; D014970:Xanthines / Q000378:metabolism / Q000494:pharmacology*
D002414:Cations, Monovalent; D004232:Diuretics; D011983:Receptors, Purinergic; D014970:Xanthines; D012964:Sodium; D000241:Adenosine; D011188:Potassium