Chemically stable homocinnamyl analogues of the leukotrienes: synthesis and preliminary biological evaluation.
The synthesis and biological characterization of a series of stable leukotriene analogues (2) are reported. They are derivatives of (5S,6R,7Z)-6-peptidyl-5-hydroxy-9-phenyl-7-nonenoic acid, in which the phenyl group is variously substituted with a heptanyl, 2-heptenyl, or hexanyloxy chain (R1) and the peptide is either glutathionyl, cysteinylglycinyl, or cysteinyl. The most potent agonist is (5S,6R,7Z)-6-S-glutathionyl-5-hydroxy-9-(4-heptanylphenyl)-7 -nonenoic acid. This analogue has an EC50 value of 74.5 nM, in the presence of 1-serine borate (45 mM), on guinea pig tracheal spirals. The agonist activity of the cysteinylglycinyl- and the cysteinyl-substituted analogues was inhibited by FPL-55712. Three of the analogues were weak leukotriene antagonists in vitro on guinea pig tracheal spirals. The most potent of these was (5S,6R,7Z)-6-S-cysteinyl-5-hydroxy-9-(2-heptanylphenyl)-7-++ +nonenoic acid. At 10 microM, this analogue inhibited by 28% the contraction induced by 8 nM LTE4.
D000626:Aminopeptidases / Q000037:antagonists & inhibitors; D000818:Animals; D002217:Carbachol / Q000494:pharmacology; D002934:Cinnamates / Q000138:chemical synthesis / Q000494:pharmacology; D006168:Guinea Pigs; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D013189:SRS-A / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014132:Trachea / Q000502:physiology; D005723:gamma-Glutamyltransferase / Q000037:antagonists & inhibitors
D002934:Cinnamates; D007202:Indicators and Reagents; D013189:SRS-A; D002217:Carbachol; D005723:gamma-Glutamyltransferase; D000626:Aminopeptidases