Adenosine elicits a wide variety of physiological responses via interactions with two major subtypes of extracellular receptors, designated as A1 and A2. Considerable efforts have been invested to search for selective A1 antagonists to elucidate the physiological role of adenosine. Theophylline and caffeine exert pharmacological effects primarily through adenosine receptor blockade but are virtually nonselective with weak affinity for A1 and A2 receptors. Studies of xanthine structure-activity relationships revealed that alkyl substitution at the 1- and 3-positions increases affinity for both receptors, while 8-aryl or 8-cycloalkyl substitution results in selective and potent A1 antagonists. 8-Cyclopentyl-1,3-dipropylxanthine (4) is known as the most potent A1 antagonist. To characterize the hydrophobic interactions between the 8-substituent of xanthine and the A1 receptor, we designed 8-substituted 1,3-dipropylxanthines based on compound 4 and the A1-selective 8-(2-methylcyclopropyl)-1,3-dipropylxanthine (5). This study describes 8-(dicyclopropylmethyl)-1,3-dipropylxanthine (18), a new xanthine derivative that is a selective and potent A1 antagonist with interesting pharmacological activities. We outlined synthetic methods and evaluated the A1 and A2 receptor binding affinities of derivatives. Compound 18 showed remarkable A1 affinity (Ki=3.0 nM) and selectivity (A2/A1 ratio=140), superior to compound 4. Pharmacological studies demonstrated that 18 exhibited more potent diuretic and natriuretic activities than theophylline and compound 4, and a stronger protective effect against glycerol-induced acute renal failure, which was better than furosemide. In conclusion, 8-(dicyclopropylmethyl)-1,3-dipropylxanthine (18, KF-15372) is the most potent and selective adenosine A1 receptor antagonist reported to date. The physiological role of adenosine A1 receptors in the kidney and detailed pharmacological activities of 18 are under active study.