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: R G Van Inwegen, G W Nuss, G W Carnathan
• Journal: Life sciences (Life Sci) Vol. 44 Issue 12 Pg. 799-807 ( 1989) ISSN: 0024-3205 [Print] Netherlands
• PMID: 2539543 (Publication Type: Comparative Study, Journal Article)

Chemical References

• Azoles
• Quinolines
• SRS-A
• Tetrazoles
• RG 12525
• Leukotriene E4

Topics

• Anaphylaxis (drug therapy, etiology)
• Animals
• Azoles (pharmacology)
• Binding, Competitive
• Bronchial Diseases (drug therapy, etiology)
• Cell Membrane (metabolism)
• Constriction, Pathologic (etiology)
• Guinea Pigs
• Hypersensitivity (drug therapy, etiology)
• Leukotriene E4
• Lung (drug effects, physiology)
• Male
• Muscle Contraction (drug effects)
• Quinolines (pharmacology, therapeutic use)
• SRS-A (analogs & derivatives, antagonists & inhibitors, metabolism, pharmacology)
• Tetrazoles (pharmacology, therapeutic use)