Important contribution of the methylene part of LTB4 toward binding affinity to the LTB4 receptors and rise in intracellular-free calcium concentration.
In order to examine a role of the C(16)-C(20) methylene part of leukotriene B4 (LTB4) toward the activation of leukocytes, we synthesized the LTB4-analogues in which the length of the C(16)-C(20) part of LTB4 is varied systematically while the two hydroxyl groups at C(5) and C(12) positions and the 6(Z), 8(E), 10(E) conjugated triene unit remained untouched. We examined their binding affinity to the LTB4 receptors present in the rat polymorphonuclear leukocytes (PMNLs) and their ability to raise intracellular-free calcium concentration ([Ca2+]i) in the rat PMNLs loaded with fura-2. As the length of the chain of LTB4 was increased or decreased one by one, the binding affinity to the LTB4 receptors diminished, and the analogues of more than three carbon atoms shorter chain were of about three log order less activity than LTB4. The biological potency as assessed in [Ca2+]i rises pararelled that of the binding affinity to the PMNL membrane. These results indicate that the C(16)-C(20) part of LTB4 plays important role for the activity. In a similar way we prepared the LTB4-analogues of a different chain length between C(2)-C(4) of LTB4 and tested their biological activity. We found that the C(2)-C(4) part of LTB4 also affects the activity.
Kobayashi
Y
Y
Department of Biomolecular Engineering, Tokyo Institute of Technology, Yokohoma, Japan.
Shimazaki
T
T
Kawajiri
K
K
Shimizu
T
T
Seyama
Y
Y
Sato
F
F
D000818:Animals; D002118:Calcium / Q000032:analysis*; D005260:Female; D006168:Guinea Pigs; D007975:Leukotriene B4 / Q000737:chemistry / Q000378:metabolism*; D008168:Lung / Q000378:metabolism; D009504:Neutrophils / Q000378:metabolism*; D051381:Rats; D018102:Receptors, Leukotriene B4 / Q000378:metabolism*; D013154:Spleen / Q000378:metabolism; D013237:Stereoisomerism; D013552:Swine
D018102:Receptors, Leukotriene B4; D007975:Leukotriene B4; D002118:Calcium