Adenosine A1 antagonists. 2. Structure-activity relationships on diuretic activities and protective effects against acute renal failure.
Adenosine A1 antagonists. 2. Structure-activity relationships on diuretic activities and protective effects against acute renal failure.
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腺苷 A1 拮抗剂。
DOI：
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发表时间：
1992
影响因子：
7.3
通讯作者：
T. Kawakita
中科院分区：
文献类型：
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作者：
F. Suzuki;J. Shimada;H. Mizumoto;A. Karasawa;K. Kubo;H. Nonaka;A. Ishii;T. Kawakita
研究黄嘌呤或非黄嘌呤腺苷拮抗剂的利尿活性及其对甘油诱导的大鼠急性肾衰竭的改善作用，以阐明肾脏中腺苷受体的生理和病理功能。多种腺苷拮抗剂的利尿和钠尿活性首次系统地阐明了A1受体的阻断在钠和水的排泄中比A2受体的阻断更重要，并支持了肾内内源性腺苷水平直接增强肾小管钠重吸收的假设。 8-取代黄嘌呤在急性肾衰竭中的构效关系研究表明，腺苷A1受体的激活是发生肾衰竭的重要因素。一系列8-(3-去金刚烷基)黄嘌呤类化合物表现出极强的利尿和利尿钠排泄活性（24; 2.5微克/千克，口服，治疗大鼠尿排泄值与对照大鼠尿排泄值之比= 1.69，治疗大鼠Na+/K+与对照大鼠Na+/K+之比= 1.76）和对甘油诱导的强效改善作用。急性肾衰竭（24；10微克/公斤，腹腔注射，55%抑制）。从我们对结构-活性关系的详细研究中，我们可以推测肾脏和大脑之间可能存在腺苷 A1 受体的一些组织差异，并且腺苷拮抗剂的作用位点在两种肾脏药理学测定中可能不同。选择 1,3-二丙基-8-(3-去甲金刚烷基)黄嘌呤，KW-3902 (24) 进行进一步研究，并正在开发作为治疗急性肾衰竭的药物。
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.