Visualization and comparison of molecular dynamics simulations of leukotriene C4, leukotriene D4, and leukotriene E4.

Molecular dynamics simulations of leukotriene C4 (LTC4), leukotriene D4 (LTD4), and leukotriene E4 (LTE4) were carried out, and the data were visualized in an animated video format. Three-dimensional ghost images show the positions of the heavy atoms of all three molecules throughout the simulations. The ghost images can be superimposed to give a single three-dimensional image in which the shapes of the most populated conformers of each molecule are apparent and can be compared. Leukotriene D4 was found to occupy mostly T-shaped conformations, while LTC4 occupied mostly cup-shaped conformations, and LTE4 occupied a wide range of conformations spanning the LTD4 and LTC4 types. Digital filtering and graphing of the internal geometries of the molecules as a function of time revealed differences in dynamic behavior. The results are discussed in light of current knowledge about leukotriene receptors.

Leukotriene B4 receptor antagonists: the LY255283 series of hydroxyacetophenones.

A series of hydroxyacetophenones was prepared for evaluation as leukotriene B4 (LTB4) receptor antagonists, culminating in 1-[5-ethyl-2-hydroxy-4-[[6-methyl-6-(1H-tetrazol-5- yl)heptyl]oxy]phenyl]ethanone (compound 35, LY255283). Using an assay for inhibition of specific [3H]LTB4 binding to human PMN, we found that substitution of a nonpolar substituent in the 5-position was required for activity. Best activity was realized with hydrogen in the 3-position, hydroxyl in the 2-position, short chain alkyl ketone in the 1-position, and a six- or eight-carbon chain linking the oxygen in the 4-position with an unsaturated terminal function. Compound 35, having an IC50 of 87 nM in the binding assay, was chosen for further preclinical evaluation.

Development of a series of phenyltetrazole leukotriene D4 (LTD4) receptor antagonists.

A hypothetical model for receptor binding of leukotriene D4 (LTD4) was deduced from conformational analysis of LTD4 and from the structure-activity relationships (SAR) of known LTD4 receptor antagonists. A new structural series of LTD4 receptor antagonists exemplified by 5-[4-(4-phenylbutoxy)phenyl]-2-[4-(tetrazol-5-yl)butyl]-2H-t etrazole was designed in which a phenyltetrazole moiety was incorporated as a receptor binding equivalent of the triene unit of LTD4. A number of these phenyltetrazoles were prepared and found to possess LTD4 receptor antagonist activity. The structure-activity relationship (SAR) of this series is described.

Leukotriene receptor on U-937 cells: discriminatory responses to leukotrienes C4 and D4.

Dimethyl sulfoxide (DMSO)-differentiated U-937 cells develop cell surface receptors for leukotrienes that, when stimulated, initiate a transient increase in intracellular calcium concentration [( Ca2+]i). We investigated the calcium transient that occurs after addition of leukotriene C4 (LTC4) to determine whether it occurs due to 1) the bioconversion of LTC4 to leukotriene D4 (LTD4), which then acts at the LTD4 receptor; 2) the direct action of LTC4 at the LTD4 receptor; or 3) the action of LTC4 at a receptor selective for LTC4. Bioconversion of [3H]LTC4 to [3H]LTD4 was inhibited by 98% when DMSO-differentiated U-937 cells were incubated with 10 mM AT-125 compared with control cells. The dose-response curve for LTC4, with [Ca2+]i as the index of response, was parallel to that for LTD4 but was significantly (P less than 0.0001) shifted 1.6 +/- 0.11 log units to the right. AT-125 did not change the response to LTD4 but the LTC4 dose-response curve was shifted on additional 1.7 logo units to the right. The antagonists SKF 104353 (1 microM) and LY 171883 (10 microM) shifted the dose-response curve for LTD4 3.0 +/- 0.23 and 2.5 +/- 0.23 log units, respectively, to the right and completely inhibited the change in [Ca2+]i due to LTC4 in the presence of 10 mM AT-125. Molecular modeling studies demonstrated a striking difference in the spatial configuration of LTC4 and LTD4, likely accounting for the ability of cell surface receptors to discriminate between the effects of these two molecules.(ABSTRACT TRUNCATED AT 250 WORDS)