title: Antagonism of peptidoleukotrienes and inhibition of systemic anaphylaxis by RG 12525 in guinea pigs.
abstract: RG 12525 was determined to be a specific, competitive and orally effective antagonist of the peptidoleukotrienes, LTC4, LTD4 and LTE4, in several assays utilizing guinea pigs. In vitro, RG 12525 competitively inhibited 3H-LTD4 binding to lung membranes (Ki = 3.0 +/- 0.3 nM) and competitively antagonized the spasmogenic activity of LTC4, LTD4 and LTE4 on lung strips (KB values = 3 nM) with greater than 8000 fold selectivity. In vivo, RG 12525 orally inhibited LTD4 induced wheal formation (ED50 = 5 mg/kg with a t1/2 = 10 hrs at 9 mg/kg), LTD4 induced bronchoconstriction (ED50 = 0.6 mg/kg), and anaphylactic death (ED50 = 2.2 mg/kg with a t1/2 = 7 hrs at 10 mg/kg) and antigen induced bronchoconstriction (ED50 = 0.6 mg/kg). RG 12525 represents a significant improvement in receptor affinity and oral efficacy and thus, is a valuable pharmacological tool to evaluate peptidoleukotrienes in allergic diseases.
authors.affiliation: Department of Immunology, Rorer Central Research, Horsham, PA 19044.
authors.forename: R G
authors.initials: RG
authors.lastname: Van Inwegen
authors.forename: G W
authors.initials: GW
authors.lastname: Nuss
authors.forename: G W
authors.initials: GW
authors.lastname: Carnathan
mesh_terms: D000707:Anaphylaxis / Q000188:drug therapy / Q000209:etiology*; D000818:Animals; D001393:Azoles / Q000494:pharmacology*; D001667:Binding, Competitive; D001982:Bronchial Diseases / Q000188:drug therapy / Q000209:etiology; D002462:Cell Membrane / Q000378:metabolism; D003251:Constriction, Pathologic / Q000209:etiology; D006168:Guinea Pigs; D006967:Hypersensitivity / Q000188:drug therapy / Q000209:etiology; D017999:Leukotriene E4; D008168:Lung / Q000187:drug effects / Q000502:physiology; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D011804:Quinolines / Q000494:pharmacology* / Q000627:therapeutic use; D013189:SRS-A / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000494:pharmacology; D013777:Tetrazoles / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D001393:Azoles; D011804:Quinolines; D013189:SRS-A; D013777:Tetrazoles; C059101:RG 12525; D017999:Leukotriene E4