Biological activity of leukotriene B4 analogs: inhibition of guinea pig eosinophil migration in vitro by the 2,6-disubstituted pyridine analogs U-75,302 and U-75,485.
A "late phase" antigen-induced bronchoalveolar eosinophilia has been demonstrated in ovalbumin sensitized guinea pigs (1,2). This in vivo response to antigen inhalation can be inhibited by a 2,6-disubstituted pyridine analog of LTB4, U-75,302(2) (3). In the present study, the mechanism of the drug action was studied by assessing the activity of U-75,302 and a second analog, U-75,485 to displace [3H]-leukotriene B4 binding at the guinea pig eosinophil membrane, as well as their action as chemoattractants or inhibitors of the directional migration of guinea pig eosinophils in vitro. Radioligand competition experiments demonstrated that both analogs interacted strongly with the high affinity LTB4 binding sites on guinea pig eosinophil membrane. Both analogs are powerful chemoattractants for guinea pig eosinophils since they induced directional migration of guinea pig eosinophils when administered alone. In addition, when the cells were treated with either analog and their chemotaxis response was measured in response to a natural chemoattractant, both U-75,302 and U-75,485 at concentrations of 0.1 to 100 microM dose dependently inhibited the LTB4 induced chemotaxis response. The EC50s obtained for U-75,302 and U-75,485 as inhibitors of LTB4 induced guinea pig eosinophil chemotaxis were estimated to be 11.5 +/- 5.5 microM and 5.4 +/- 2.5 microM respectively. Under the same conditions, they had no significant effect upon eosinophil migration induced by zymosan activated plasma at concentrations below 100 microM. We suggest that the inhibition of antigen-induced eosinophil infiltration in guinea pig airway in vivo by U-75,302 or U-75,485 may be a result of partial antagonism or desensitization at the LTB4 receptor level of guinea pig eosinophils.
Taylor
B M
BM
Department of Hypersensitivity Diseases Research, Upjohn Company, Kalamazoo, Michigan 49001.
Crittenden
N J
NJ
Bruden
M N
MN
Wishka
D G
DG
Morris
J
J
Richards
I M
IM
Sun
F F
FF
D000818:Animals; D001249:Asthma / Q000503:physiopathology; D001667:Binding, Competitive; D002465:Cell Movement / Q000187:drug effects; D002630:Chemotactic Factors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004804:Eosinophils / Q000187:drug effects* / Q000502:physiology; D005233:Fatty Alcohols / Q000494:pharmacology*; D005260:Female; D006018:Glycols / Q000494:pharmacology*; D006168:Guinea Pigs; D007975:Leukotriene B4 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology*; D011971:Receptors, Immunologic / Q000378:metabolism*; D018102:Receptors, Leukotriene B4
D002630:Chemotactic Factors; D005233:Fatty Alcohols; D006018:Glycols; D011725:Pyridines; D011971:Receptors, Immunologic; D018102:Receptors, Leukotriene B4; C072776:3-(6-(3-hydroxy-1,5-undecadienyl)-2-pyridinyl)-oxiranebutanol; C062137:U 75302; D007975:Leukotriene B4