title: Pharmacologic profile of chemically stable analogs of peptide leukotrienes.
abstract: 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)
mesh_terms: 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*
chemical_list: D002867:Chromones; D018077:Receptors, Leukotriene; D011982:Receptors, Prostaglandin; D013189:SRS-A; D017999:Leukotriene E4; C006312:FPL 55712