Adenosine A1 antagonists. 2. Structure-activity relationships on diuretic activities and protective effects against acute renal failure

Abstract

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.

Purinergic signalling in the kidney in health and disease

“…Cisplatin upregulates A 1 receptors in rat kidney [25] and A 1 receptor antagonists have a protective effect against cisplatininduced acute kidney injury in rats [107]. Adenosine antagonists have protective effects against acute renal failure [156, 253,358]. A 1 receptor antagonists are effective against the development of nephrotoxicity by cyclosporine, an immunosuppressive agent [18].…”

Protective Effects of KW-3902, an Adenosine A1-Receptor Antagonist, against Cisplatin-Induced Acute Renal Failure in Rats

“…KW-3902 (8-(noradamantan-3-yl)-1,3-dipropylxanthine) is a newly synthesized specific adenosine A,-receptor antagonist and the most potent one reported to date (14). In receptor-binding studies, dissociation constant values of KW-3902 for adenosine A,-receptor and A2-receptor are 1.3 and 380 nM, respectively (14).…”

The utilization of a unified pharmacophore query in the discovery of new antagonists of the adenosine receptor family

“…[3][4][5] A unified pharmacophore model based on steric and electrostatic fit of various A 3 receptor antagonists has recently been reported by Moro et al (1998). 6 Adenosine receptor antagonists having selectivity for A 1 and A 2 A receptors have been under development as anti-arhythmic, 7 renoprotective, 8 anti-Parkinson's, 9 anti-depressant, 10 and cognition enhancing 11 drugs. Recently, chemical leads for A 2 B receptor-selective xanthines, which are predicted to have potential as anti-asthmatic agents, 12,13 have been reported.…”