Pharmacologic profile of chemically stable analogs of peptide leukotrienes.
Peptide leukotrienes are potent constrictors of airway smooth muscle but lack chemical stability. Replacement of the natural triene backbone of leukotrienes with 9-(x-heptylphenyl)-7-nonenoic acid (x = 2, 3, or 4) renders these analogs chemically stable and pharmacologically active. The para, meta and ortho substitutions of the heptyl (C7H15) moiety were combined with the different leukotriene peptide substitutions of glutathionyl, C-peptide of leukotriene C4, cysteinylglycinyl, D-peptide of leukotriene D4, and cysteinyl, E-peptide of leukotriene E4 rendering nine active analogs. The pharmacology of these analogs was evaluated in isolated guinea-pig tracheal strips. The para-substituted C-peptide analog was the most potent; however, it was 100-fold less potent than leukotriene C4. The contractile activities of the para- and meta-substituted C-peptide analogs were enhanced by L-serine borate (45 mM), indicating they were substrates for gamma-glutamyl transpeptidase. FPL55712 (10 microM) failed to antagonize the substituted C-peptide analogs independent of the presence of L-serine borate. The contractile activities of the three substituted D-peptide analogs were enhanced by L-cysteine, indicating they are all substrates for aminopeptidase. The para-substituted D-peptide analog was the most potent D-peptide analog, but it was 10- and 1,000-fold less active than the para-substituted C-peptide analog and leukotriene D4, respectively. The para- and meta-substituted E-peptide analogs were approximately 1,000-fold less potent than leukotriene E4, and like the substituted D-peptide analogs, they were antagonized by FPL55712. In contrast, the ortho-substituted E-peptide analog was devoid of intrinsic activity but antagonized leukotriene E4-induced contractions.(ABSTRACT TRUNCATED AT 250 WORDS)
D000818:Animals; D002867:Chromones / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D066298:In Vitro Techniques; D017999:Leukotriene E4; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D018077:Receptors, Leukotriene; D011982:Receptors, Prostaglandin / Q000187:drug effects; D013189:SRS-A / Q000031:analogs & derivatives* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014132:Trachea / Q000187:drug effects*
D002867:Chromones; D018077:Receptors, Leukotriene; D011982:Receptors, Prostaglandin; D013189:SRS-A; D017999:Leukotriene E4; C006312:FPL 55712