title: Vasopeptidase-activated latent ligands of the histamine receptor-1.
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.
authors.affiliation: Department of Biochemistry, University of Colorado Denver, Aurora, CO 80045, USA.
authors.forename: Lajos
authors.initials: L
authors.lastname: Gera
authors.forename: Caroline
authors.initials: C
authors.lastname: Roy
authors.forename: Xavier
authors.initials: X
authors.lastname: Charest-Morin
authors.forename: François
authors.initials: F
authors.lastname: Marceau
mesh_terms: D000818:Animals; D019390:Arrestins / Q000378:metabolism; D001920:Bradykinin / Q000737:chemistry / Q000378:metabolism; D016466:CHO Cells; D017332:Cetirizine / Q000737:chemistry / Q000378:metabolism; D003412:Cricetulus; D057809:HEK293 Cells; D006632:Histamine / Q000378:metabolism; D006633:Histamine Antagonists / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008024:Ligands; D010447:Peptide Hydrolases / Q000378:metabolism*; D010455:Peptides / Q000378:metabolism*; D011355:Prodrugs / Q000378:metabolism*; D011738:Pyrilamine / Q000378:metabolism; D011869:Radioligand Assay; D043782:Receptor, Bradykinin B2 / Q000378:metabolism*; D011969:Receptors, Histamine H1 / Q000378:metabolism*; D014471:Umbilical Veins / Q000502:physiology; D014661:Vasoconstriction; D000071557:beta-Arrestins
chemical_list: D019390:Arrestins; D006633:Histamine Antagonists; D008024:Ligands; D010455:Peptides; D011355:Prodrugs; D043782:Receptor, Bradykinin B2; D011969:Receptors, Histamine H1; D000071557:beta-Arrestins; D006632:Histamine; D010447:Peptide Hydrolases; D011738:Pyrilamine; D001920:Bradykinin; D017332:Cetirizine
keywords: Aminopeptidase N; Angiotensin converting enzyme; Bradykinin B(2) receptor; Histamine H(1) receptor; Human umbilical vein; Prodrug