U19052 (ICIAm): a novel leukotriene analog which antagonizes LTC4, LTD4, and LTE4.
Chemically stable analogs of peptide leukotrienes (LT) have been developed in our laboratories by replacement of the natural triene backbone with a C7H15 substituted aromatic moiety (1). These analogs are potent agonists of airway smooth muscle. Substitution in the peptide region resulted in U19052, an LT receptor antagonist. U19052 antagonized LT-induced contractions of guinea-pig tracheal spirals in a concentration-related manner. The pA2 values versus LTD4 and LTE4 were 6.0 and 5.7, respectively, with slopes which were not significantly different from unity. LTC4-induced contractions were antagonized by U19052 with a pKB of 5.6 obtained either in the absence or presence of L-serine borate. In contrast, carbachol and histamine concentration-response curves were not altered by U19052. LTD4 or LTE4 contractions of isolated guinea-pig ileum were antagonized by U19052 with pKB values of 7.2. The results indicate that potent selective LT antagonists can be developed from stable analogs of leukotrienes. U19052, an example of this series, appears to be as effective in antagonizing LTC4- as well as LD4- and LTE4-induced contractions in guinea-pig tracheal spirals.
Snyder
D W
DW
Department of Pharmacology, Stuart Pharmaceuticals, Division ICI Americas Inc. Wilmington, DE 19897.
Bernstein
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PR
D000818:Animals; D002217:Carbachol / Q000494:pharmacology; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology*; D006168:Guinea Pigs; D006632:Histamine / Q000494:pharmacology; D007082:Ileum / Q000187:drug effects; D066298:In Vitro Techniques; D017999:Leukotriene E4; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D013189:SRS-A / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors*; D014132:Trachea / Q000187:drug effects
D005231:Fatty Acids, Unsaturated; D013189:SRS-A; C057510:U 19052; D017999:Leukotriene E4; D006632:Histamine; D002217:Carbachol