Structure elucidation of fluorescent H₁ antihistamines by ultraviolet resonance Raman spectroscopy: solvent structures of tripelennamine and mepyramine

Abstract

Ultraviolet Resonance Raman (UVRR) spectroscopy -a Raman technique that combines high sensitivity with high selectivity and does not suffer from background fluorescence -is applied to the fluorescent H 1 antihistamines tripelennamine (TRP) and mepyramine (MEP) in aqueous solution to elucidate their molecular structure as a function of pH. In a previous investigation of these compounds (C. Tardioli, G. Gooijer G. van der Zwan, J. Phys. Chem. B, 113, (2009), 6949), the presence of gauche conformers caused by intramolecular interaction of the protonated alkylamine tail with the pyridine nitrogen was assumed to explain the pH dependence of the fluorescence properties. In order to validate this assumption, use is made of the resonant excitation of the aminopyridine chromophore in TRP and MEP. In that way, structural information associated with the vibrations of that moiety can be obtained, and the changes it undergoes upon protonation can be monitored. Assignment of the vibrations was achieved with the help of a number of other compounds, and quantum chemical calculations. N,N-Dimethylaminopyridine (2DMP) and its mono-protonated form (2DMPH + ) were investigated, since this molecule was shown to have optical properties closely resembling those of the aminopyridine moiety in TRP and MEP. Assignment of the vibrations of 2DMP was accomplished by comparison with the resonance Raman spectra of two other reference structures, 2-aminopyridine and dimethylaniline -for which ordinary Raman data are available -and by Gaussian calculations. UVRR spectra of TRP and MEP could be readily interpreted on the basis of vibrational assignments of the parent chromophores, i.e. 2DMP and 2DMPH + . Vibrations of the aminopyridine chromophore in TRP and MEP at neutral pH, where the aminoalkyl chain is protonated, are modified when compared to the vibrational pattern recorded for a fully neutral molecule in alkaline solution. This implies an electronic redistribution in the ring originating from internal hydrogen bonding between the aminoalkyl tail and the aminopyridine chromophore.

pH-Dependent Complexation of Histamine H1 Receptor Antagonists and Human Serum Albumin Studied by UV Resonance Raman Spectroscopy

“…At pH 9 only 50% of the molecules will be protonated at the tail (pK a = 8.9). 2,3 Antihistamine/HSA Complex and K a Evaluation. The pH influence on the binding of TRP and MEP to HSA was first investigated by means of UV absorption spectroscopy.…”

“…We recently made use of the same technique to successfully investigate the solution conformation of TRP and MEP. 2 We showed that there is a definite influence of the protonated ethylamino chain on the chemical and photophysical properties of these molecules. Most probably for TRP and MEP the HSA−ligand interaction is affected by their solution conformations, which in turn are dependent on the protonation state of the tail.…”

“…In a previous paper, 2 we selected two antihistamines, tripelennamine (TRP) and mepyramine (MEP), as representative, for their optical properties. As many antihistamines of that class, and as indicated in Figure 1, they share as a common feature an ethylamino chain with a strongly basic (pK a ≈ 9) nitrogen atom at the end.…”

“…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.…”

Recent advances in linear and nonlinear Raman spectroscopy. Part VI

“…carried out resonance Raman scattering with 239.5‐ and 245.9‐nm excitation wavelengths and a DFT theoretical analysis of the photodissociation dynamics of formanilide in S 3 state . Tardioli and co‐workers elucidated the structure of fluorescent H1 antihistamines by ultraviolet resonance Raman spectroscopy to learn more about the solution structures of tripelennamine and mepyramine . Wei et al .…”