Vasopeptidase-activated latent ligands of the histamine receptor-1

Authors: Gera, Lajos; Roy, Caroline; Charest-Morin??, Xavier; Marceau, François
Abstract: Whether peptidases present in vascular cells can activate prodrugs active on vascular cells has been tested with 2 potential latent ligands of the histamine H1 receptor (H1R). First, a peptide consisting of the antihistamine cetirizine (CTZ) condensed at the N-terminus of ε-aminocaproyl-bradykinin (εACA-BK) was evaluated for an antihistamine activity that could be revealed by degradation of the peptide part of the molecule. CTZ-εACA-BK had a submicromolar affinity for the BK B2 receptor (B2R; IC50 of 590 nM, [(3)H]BK binding competition), but a non-negligible affinity for the human H1 receptor (H1R; IC50 of 11 μM for [(3)H]pyrilamine binding). In the human isolated umbilical vein, a system where both endogenous B2R and H1R mediate strong contractions, CTZ-εACA-BK exerted mild antagonist effects on histamine-induced contraction that were not modified by omapatrilat or by a B2R antagonist that prevents endocytosis of the BK conjugate. Cells expressing recombinant ACE or B2R incubated with CTZ-εACA-BK did not release a competitor of [(3)H]pyrilamine binding to H1Rs. Thus, there is no evidence that CTZ-εACA-BK can release free cetirizine in biological environments. The second prodrug was a blocked agonist, L-alanyl-histamine, potentially activated by aminopeptidase N (APN). This compound did not compete for [(3)H]pyrilamine binding to H1Rs. The human umbilical vein contractility assay responded to L-alanyl-histamine (EC50 54.7 μM), but the APN inhibitor amastatin massively (17-fold) reduced its apparent potency. Amastatin did not influence the potency of histamine as a contractile agent. One of the 2 tested latent H1R ligands, L-alanyl-histamine, supported the feasibility of pro-drug activation by vascular ectopeptidases
Document Type: Article de recherche
Issue Date: 1 November 2013
Open Access Date: 17 November 2017
Document version: AM
Permalink: http://hdl.handle.net/20.500.11794/15874
This document was published in: International Immunopharmacology, Vol. 17 (3), 677–683 (2013)
https://doi.org/10.1016/j.intimp.2013.08.014
Elsevier
Alternative version: 10.1016/j.intimp.2013.08.014
24016859
Collection:Articles publiés dans des revues avec comité de lecture

Files in this item:
SizeFormat 
143.pdf757.58 kBAdobe PDFView/Open
All documents in CorpusUL are protected by Copyright Act of Canada.