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A number of new 1,4-benzodiazepin-2-one-based gastrin/CCK-B receptor antagonists related to the archetypal analogue L-365,260, and more closely to the recently reported compound YM022, have been synthesized and evaluated for biological activity. The compounds were screened for their ability to inhibit the binding of [125I]CCK-8 to gastrin/CCK-B receptors prepared from rat brains and that of [3H]L-364,718 to CCK-A receptors from rat pancreas, and were shown to be potent and selective ligands for the gastrin/CCK-B receptor. Functional studies in vivo demonstrated the compounds to be antagonists of the receptor as evidenced by their ability to inhibit pentagastrin-induced gastric acid secretion in anesthetized rats. More extensive evaluation in vivo included determination of ED50 values in the rat acid secretion model for selected compounds and an examination of the effect of these compounds on pentagastrin-induced gastric acid secretion in Heidenhain pouch dogs following oral and intravenous administration. Two compounds, i.e. (3R)-N-[1-[(tert-butylcarbonyl)methyl]-2,3-dihydro-2-oxo-5-(2-pyri dyl) -1H-1,4-benzodiazepin-3-yl]-N'-[3-(methylamino)phenyl]urea, 15c (YF476), and (3R)-N-[1-[(tert-Butylcarbonyl)methyl]-2,3-dihydro-2-oxo-5- (2-pyridyl)-1H-1,4-benzodiazepin-3-yl]-N'-[3-(dimethylamino)phenyl ]urea hydrochloride, 15d, showed potent dose-dependent effects in both models with the former showing excellent oral bioavailability and an ED50 of 21nmol/kg po in dogs. 15c is currently under clinical investigation for the treatment of gastro-oesophagal reflux disease (GORD).

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The build-up of phosphorus (P) in soil is a major factor limiting the operating life of a wastewater land treatment system. In this study, effects of long-term wastewater application on changes in chemical properties, P profiles, and P adsorption capacity were evaluated in soils of the Muskegon wastewater land treatment plant that has been treating wastewater for > 30 years. Results indicate that the major soil properties have been changed. In the 15 cm topsoil, the pH increased from ∼ 5-6 in 1973 to ∼ 7.4-7.8 in 2003; the soil's total organic carbon (TOC) increased by 10-71 %; and the level of exchangeable Ca in 2003 is 8-9 times higher than that in 1973. The amount of Ca/Mg absorbed in the soil affects the P adsorption capability of the soil; Ca-and Mg-bound P accounts for > 70 % of the total P adsorbed in the soil. The net P accumulated in the Rubicon soil increased from ∼ 700 in 1993 to ∼ 1345 kg/ha soil in 2001, but the plant available P varied between ∼ 100-500 kg/ha soil during the same period, indicating a large amount of the applied P has become the fixed P that is unavailable to plants. P sorption in the soil consists of a fast adsorption and a slow transformation process. The soil's maximum P sorption capacity (P max ) (based on 1-day isotherm tests) has been increased by ∼ 2-4 times since 1973; the actual P max of the Muskegon soils could be much higher than the 1-day P max . Therefore, the life expectancy of the Muskegon system has been extended significantly with the application of wastewater.