We report the identification of a novel pharmacological profile for the leukotriene (LT)C-4 binding site we previously identified in human lung parenchyma (HLP). We used a series of classic cysteinyl-LT (CysLT)(1) receptor antagonists belonging to different chemical classes and the dual CysLT(1)-CysLT(2) antagonist BAY u9773 for both binding and functional studies. Because the presence of (S)-decyl-glutathione interfered with cysteinyl-LT binding, with a kinetic protocol we avoided the use of this compound. By means of heterologous dissociation time courses, we demonstrated that zafirlukast, iralukast, and BAY u9773 selectively competed only for H-3-LTD4 binding sites, whereas pobilukast, pranlukast, and CGP 57698 dissociated both H-3-LTC4 and H-3-LTD4 from their binding sites. Thus, with binding studies, we have been able to identify a pharmacological profile for LTC4 distinct from that of LTD4 receptor (CysLT(1)) in HLP. On the contrary, in functional studies, all of the classic antagonists tested were able to revert both LTC4- and LTD4-induced contractions of isolated HLP strips. Thus, LTD4 and LTC4 contract isolated HLP strips through the same CysLT1 receptor. The results of kinetic binding studies, coupled to a sophisticated data analysis, confirm our hypothesis that HLP membranes contain two cysteinyl-LT high-affinity binding sites with different pharmacological profiles. In functional studies, however, LTD4- and LTC4-induced contractions are mediated by the same CysLT(1) receptor. In conclusion, the specific LTC4 high-affinity binding site cannot be classified as one of the officially recognized CysLT receptors, and it is not implicated in LTC4-induced HLP strip contractions.

A kinetic binding study to evaluate the pharmacological profile of a specific leukotriene C-4 binding site not coupled to contraction in human lung parenchyma / S. Ravasi, V. Capra, M. Mezzetti, S. Nicosia, G. Rovati. - In: MOLECULAR PHARMACOLOGY. - ISSN 0026-895X. - 57:6(2000), pp. 1182-1189.

A kinetic binding study to evaluate the pharmacological profile of a specific leukotriene C-4 binding site not coupled to contraction in human lung parenchyma

S. Ravasi;V. Capra;S. Nicosia;G. Rovati
2000

Abstract

We report the identification of a novel pharmacological profile for the leukotriene (LT)C-4 binding site we previously identified in human lung parenchyma (HLP). We used a series of classic cysteinyl-LT (CysLT)(1) receptor antagonists belonging to different chemical classes and the dual CysLT(1)-CysLT(2) antagonist BAY u9773 for both binding and functional studies. Because the presence of (S)-decyl-glutathione interfered with cysteinyl-LT binding, with a kinetic protocol we avoided the use of this compound. By means of heterologous dissociation time courses, we demonstrated that zafirlukast, iralukast, and BAY u9773 selectively competed only for H-3-LTD4 binding sites, whereas pobilukast, pranlukast, and CGP 57698 dissociated both H-3-LTC4 and H-3-LTD4 from their binding sites. Thus, with binding studies, we have been able to identify a pharmacological profile for LTC4 distinct from that of LTD4 receptor (CysLT(1)) in HLP. On the contrary, in functional studies, all of the classic antagonists tested were able to revert both LTC4- and LTD4-induced contractions of isolated HLP strips. Thus, LTD4 and LTC4 contract isolated HLP strips through the same CysLT1 receptor. The results of kinetic binding studies, coupled to a sophisticated data analysis, confirm our hypothesis that HLP membranes contain two cysteinyl-LT high-affinity binding sites with different pharmacological profiles. In functional studies, however, LTD4- and LTC4-induced contractions are mediated by the same CysLT(1) receptor. In conclusion, the specific LTC4 high-affinity binding site cannot be classified as one of the officially recognized CysLT receptors, and it is not implicated in LTC4-induced HLP strip contractions.
Settore BIO/14 - Farmacologia
MOLECULAR PHARMACOLOGY
http://molpharm.aspetjournals.org/content/57/6/1182.long
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/180084
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