2-(aminoacylamino)benzophenones: farnesyltransferase inhibition and antimalarial activity.

The use of amino acids as acyl substitutents at the 2-amino group of our benzophenone core structure yielded compounds with mainly good to moderate farnesyltransferase inhibitory and moderate antimalarial activity. However, these farnesyltransferase inhibitors display some degree of selectivity towards malarial parasites since there was no cytotoxic activity observed at 70-80 microM.

Novel lead structures for antimalarial farnesyltransferase inhibitors.

Through the combination of nitrophenylfurylacryloyl moiety which has been designed to occupy an aryl binding site of farnesyltransferase with several AA(X)-peptidomimetic substructures some novel farnesyltransferase inhibitors were obtained. Evaluation of their antimalarial activity and some initial modifications yielded a 4-benzophenone- and a sulfonamid-based novel lead for antimalarial farnesyltransferase inhibitors.

2-(Arylpropionylamino)- and 2-(arylacryloylamino)benzophenones: farnesyltransferase inhibition and antimalarial activity.

Structural variation of the 2-acylamino moiety of some benzophenone farnesyltransferase inhibitors led to the para-trifluoromethylphenylpropionyl derivative with relatively low farnesyltransferase inhibition but considerable antimalarial activity and no cytotoxicity.

Increased phagocytic capacity of the blood, but decreased phagocytic activity per individual circulating neutrophil after an ultradistance run.

The effect of a long strenuous endurance exercise on the phagocytic function of neutrophils was examined. 9 athletes [7 males, 2 females, age: 36-68 years, body mass: 64 (SD 10) kg, height: 175 (SD 10) cm] completed a competetive 100 km run in 8:07 (median value; range: 7:29-9:50 hours). In a whole blood assay the phagocytosis of opsonized E. coli, the receptor density of the Fc gamma receptor 3 (CD16) and the complement receptor 3 (CD11b, direct immunofluorescence) of neutrophils were measured on a per cell basis by flow cytometry before and up to 3 hours after the race. The phagocytic rate (percentage of neutrophils incorporating bacteria) was unchanged after exercise, whereas the phagocytic activity (number of incorporated bacteria per cell) was significantly reduced by -34 (SD 8) % (Wilcoxon test, P < 0.001). The total phagocytic capacity of the blood increased 2-3fold post exercise. The surface antigen expressions of CD11b and CD16 were unaffected by the ultradistance run. The results indicate either a reduced phagocytic function of neutrophils on a single cell basis or the mobilization of neutrophils of the marginal pool with a lower phagocytic activity. However, after a long endurance exercise the phagocytotic capacity of the blood was enhanced due to increased cell concentrations.

[3H]tryptamine binding sites are not identical to monoamine oxidase in rat brain.

Competition binding studies, subcellular distribution, and in vitro autoradiography were employed to compare the binding in rat brain of [3H]tryptamine with two radioligands for monoamine oxidase (MAO), [3H]pargyline, and [3H]1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine ([3H]MPTP). The MAO inhibitors pargyline, clorgyline, and deprenyl all yielded biphasic competition curves versus [3H]tryptamine. At low concentrations, these drugs stimulated binding by protecting the radioligand from MAO oxidation; at considerably higher concentrations, they inhibited binding by direct competition at the [3H]tryptamine binding site. In subcellular distribution studies, [3H]tryptamine was localized preferentially to the synaptosomal fraction, whereas [3H]pargyline showed greater binding to the mitochondrial fraction. Equilibrium binding studies revealed that the potencies of a series of seven compounds at inhibiting [3H]tryptamine binding were completely different from their potencies at inhibiting [3H]MPTP binding. Finally, the autoradiographic distribution of [3H]tryptamine binding in rat brain was different from that of [3H]MPTP and [3H]pargyline. We conclude that the [3H]tryptamine binding site in rat brain is not equivalent to MAO.

[Haemodynamics and tolerance to hypoxia of the myocardium under 6%-oxygen ventilation following acute isovolaemic haemodilution in experimental animals (author's transl)]. / Hämodynamisches Verhalten und Hypoxietoleranz des Myokards unter 6%-Sauerstoffmangelbeatmung nach akuter isovolämischer Hämodilution in Tierexperiment

1. In experiments on closed chest dogs in a control group and a group of previous isovolaemic haemodiluted dogs a cardiovascular stress was produced by means of reduction of inspiratory O2 content to 6% O2--2. Under haemodilution only small changes of the heart rate, aortic pressure and dp/dtmax occurred, pointing to a decreased sympathoadrenergic response. Augmentation of LVEDP and pulmonary artery pressure is considered to be related to left ventricular insufficiency.--3. According to haemodynamic changes myocardial O2 demand in the control group during hypoxia is increasedby 120% and in contrast remains unchanged after previous haemodilution.--4. Despite the reduced oxygen content under haemodilution severe arterial hypoxemia affects mean survival time of the animals (18.5 min and 21.5 min respectively) only little. However, there is a greater variation from 11 to 26 min in the haemodiluted animals.