title: pH-dependent complexation of histamine H1 receptor antagonists and human serum albumin studied by UV resonance Raman spectroscopy.
abstract: UV resonance Raman spectroscopy was used to characterize the binding of three first-generation histamine H(1) receptor antagonists-tripelennamine (TRP), mepyramine (MEP), and brompheniramine (BPA)-to human serum albumin (HSA) at pH 7.2 and pH 9.0. Binding constants differ at these pH values, which can be ascribed to the different extent of protonation of the ethylamino side chain of the ligands. We have recently shown [Tardioli et al. J. Raman Spectrosc. 2011, 42, 1016-1024] that for the solution conformation of TRP and MEP the side chain plays an important role by allowing an internal hydrogen bond with the aminopyridine nitrogen in TRP and MEP. Results presented in this paper suggest that the existence of such molecular structures has serious biological significance on the binding affinity of those ligands to HSA. At pH 7.2, only the stretched conformers of protonated TRP and MEP bind in HSA binding site I. Using UV absorption data, we derived binding constants for the neutral and protonated forms of TRP to HSA. The neutral species seems to be conjugated to a positive group of the protein, affecting both the tryptophan W214 and some of the tyrosine (Y) vibrations. BPA, for which the structure with an intramolecular hydrogen bonded side chain is not possible, is H bound to the indole ring nitrogen of W214, of which the side chain rotates over a certain angle to accommodate the drug in site I. We propose that the protonated BPA is also bound in site I, where the Y150 residue stabilizes the presence of this compound in the binding pocket. No spectroscopic evidence was found for conformational changes of the protein affecting the spectroscopic properties of W and Y in this pH range.
authors.affiliation: Amsterdam LaserLaB, Department of Biomolecular Analysis and Spectroscopy, Vrije Universiteit, Amsterdam, The Netherlands.
authors.forename: Silvia
authors.initials: S
authors.lastname: Tardioli
authors.forename: Joost
authors.initials: J
authors.lastname: Buijs
authors.forename: Cees
authors.initials: C
authors.lastname: Gooijer
authors.forename: Gert
authors.initials: G
authors.lastname: van der Zwan
mesh_terms: D001665:Binding Sites; D001977:Brompheniramine / Q000737:chemistry; D006634:Histamine H1 Antagonists / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D006860:Hydrogen Bonding; D006863:Hydrogen-Ion Concentration; D011738:Pyrilamine / Q000737:chemistry; D011969:Receptors, Histamine H1 / Q000737:chemistry* / Q000378:metabolism; D012709:Serum Albumin / Q000737:chemistry* / Q000378:metabolism; D013056:Spectrophotometry, Ultraviolet; D013059:Spectrum Analysis, Raman; D014309:Tripelennamine / Q000737:chemistry; D014364:Tryptophan / Q000737:chemistry
chemical_list: D006634:Histamine H1 Antagonists; D011969:Receptors, Histamine H1; D012709:Serum Albumin; D014309:Tripelennamine; D014364:Tryptophan; D001977:Brompheniramine; D011738:Pyrilamine