Inhibitory effect of ONO-1078 on specific binding of peptide leukotrienes to human lung crude membrane.
We investigated the effects of ONO-1078, a newly synthesized peptide leukotriene (p-LT antagonist, on the specific binding of radiolabelled [3H]-LTC4, [3H]-LTD4 and [3H]-LTE4 to a human lung crude membrane fraction (HLMF). The binding assay was performed under conditions in which [3H]-LTC4 and [3H]-LTD4 were not metabolized by HLMF; that is, the metabolism of LTC4 to LTD4 or LTE4 was almost completely prevented by pretreating HLMF with 5 mM acivicin at 37 degrees C for 180 min, and metabolism of LTD4 to LTE4 was inhibited by including 5 mM L-cysteine and 5 mM glycine in the assay. [3H]-LTD4 specific binding was potently and concentration-dependently dissociated by ONO-1078. Its potency was 180-fold stronger than that of FPL 55712, a standardized p-LT antagonist, whereas high concentrations of ONO-1078 similar to those of FPL 55712 were required to inhibit [3H]-LTC4 specific binding. The rank order of the inhibitory potencies of p-LT agonists and antagonists for [3H]-LTD4 specific binding was LTD4 > ONO-1078 > LTE4 > LTC4 > FPI 55712. On the other hand, not only high concentrations of ONO-1078 and FPL 55712 but also more than a 100-fold excess of unlabelled LTE4 was required to inhibit [3H]-LTE4 specific binding, indicating that the binding sites do not appear to be receptors of LTE4. From these results, it is suggested that ONO-1078 is a highly potent LTD4 antagonist which is expected to be very effective on bronchial asthma.
Nabe
T
T
Department of Pharmacology, Kyoto Pharmaceutical University, Japan.
Kohno
S
S
Tanpo
T
T
Saeki
Y
Y
Yamamura
H
H
Horiba
M
M
Ohata
K
K
D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism*; D002867:Chromones / Q000494:pharmacology*; D003545:Cysteine / Q000494:pharmacology; D005998:Glycine / Q000494:pharmacology; D006801:Humans; D007555:Isoxazoles / Q000494:pharmacology; D017998:Leukotriene D4 / Q000037:antagonists & inhibitors*; D008168:Lung / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D013189:SRS-A / Q000378:metabolism*; D005723:gamma-Glutamyltransferase / Q000037:antagonists & inhibitors
D002867:Chromones; D007555:Isoxazoles; D013189:SRS-A; D017998:Leukotriene D4; C006312:FPL 55712; D005723:gamma-Glutamyltransferase; D003545:Cysteine; C006303:acivicin; C047681:pranlukast; D005998:Glycine