Analogues and fragments of secretin.

For the purpose of analytical investigation and structure/activity relationships, some secretin analogues and secretin fragments have been synthesized. HPLC comparison of the synthesized products with our synthetic secretin revealed about 2% [D-Ala17]secretin, 1% [D-Leu13]secretin and less than 1% aminoterminal degradation products. The D-Ala17 content can be eliminated if the starting material used for segment coupling (Z-Arg(Z2)-Asp(OBut)-Ser(But)-Ala-OH) has no D-Ala-contamination. In addition, traces of the rearrangement products [3-aspartoyl]-secretin and [beta-Asp3]secretin are suspected. Secretin can be degraded to several compounds by chromatography on a strong basic ion exchanger in 1% acetic acid. These products are more polar than secretin and have no biological activity. The secretin content measured by HPLC correlated well with the biological data, since the degradation products and other byproducts separated by HPLC have only a negligible influence on the pancreatic flow.

Central and peripheral action of enkephalin analogues.

Chemical modifications of enkephalins led to analogues with strongly increased biological potency. Compounds such as H-Tyr-DLys(CHO)-Gly-Phe-L-homocysteinethiolactone (Hoe 825) additionally show a remarkable split between central and peripheral action, favouring the stimulation of gastrointestinal contractions. Hoe 825 could, therefore, be useful in the treatment of conditions where gut motility is lacking in humans, especially in adynamic ileus.

Synthesis of a highly active angiotensin converting enzyme inhibitor: 2-[N-[(S)-1-ethoxycarbonyl-3-phenylpropyl]-L-alanyl]-(1S,3S,5S)-2- azabicyclo[3.3.0]octane-3-carboxylic acid (Hoe 498).

The convergent, diastereoselective synthesis of 2-[N-[(S)-1-ethoxycarbonyl-3-phenylpropyl]-L-alanyl]-(1S,3S,5S)-2- azabicyclo[3.3.0]octane-3-carboxylic acid (Hoe acid (Hoe 498), a new ACE-inhibitor with improved bioavailability and pharmacokinetics, is described.

B1-3,5-diiodotyrosine insulin: a valid tracer for insulin.

Insulin, specifically substituted at the PheB1 position with 3,5-diiodotyrosine, has been tested in several biological and immunological systems. Immunoreactivity was assessed using antisera specific for different parts of the insulin molecule. Biological activity in vitro was estimated on isolated rat fat cells. In vivo bioactivity (hypoglycaemia) and metabolism (metabolic and urinary clearance rates, half-life, apparent distribution space) were measured by infusion of the material into greyhounds. The results indicated that this B1-labelled insulin preparation was biologically fully active and, unlike randomly labelled preparations of iodoinsulin, was metabolised with kinetics indistinguishable from those of the unlabelled hormone. We suggest that this material is a valid tracer for insulin, fulfilling the criteria of high specific activity and biological identity to the native hormone.

Interference in clinical laboratory tests, with special regard to the bilirubin assay: effects of a metabolite of the new prolyl 4-hydroxylase inhibitor, Lufironil.

During the toxicological examination of the fibrosuppressive agent, Lufironil (INN), in rats a dose-dependent positive reaction for urinary bilirubin was observed. This positive reaction was found in quantitative assays, and when using test strips. The positive reaction for bilirubin in these assay systems was caused by a metabolite of Lufironil. It was not due to drug toxicity, and it was not caused by any endogenous substrate produced under the influence of Lufironil. The compound responsible for this reaction was isolated by HPLC and its structure determined by spectroscopic methods. The structure was confirmed by synthesis, starting from pyridine-2,4-dicarboxylate. The synthesized compound and the compound in urine gave an identical reaction with the test reagent for bilirubin.