β-Adrenoceptor studies. 5. 1H NMR and IR spectroscopic analysis of the conformation of the hydrohalide salts of β-adrenoceptor-blocking aryloxypropanolamines. Evidence for a seven-membered ring structure with participation of two hydrogen bonds

Article abstract of DOI:10.1021/jm00190a017

A conformational analysis of hydrohalide salts of the β-adrenoceptor antagonist toliprolol [3-(isopropylamino)-1-(3-methylphenoxy)-2-propanol)] and of its isomer 2-(isopropylamino)-3-(3-methylphenoxy)-1-propanol, in which the hydroxy and isopropylamino groups in the side chain had changed place, was performed using ¹H NMR and IR spectroscopic methods. Derivatives of both compounds in which the hydroxy group had been replaced by a methoxy group or a chloro atom were synthetized and included in the investigation as well. In addition, the β-adrenoceptor-blocking activities of the hydrochloride salts of the compounds were determined on the isolated guinea pig right atrium and tracheal strip preparation, using isoprenaline as the agonist. In an aprotic apolar medium (deuteriochloroform), the ¹H NMR spectra of all compounds studied showed an upfield shift of the ammonium protons on variation of the anion from chloride via bromide to iodide. The same phenomenon was seen with the hydroxyl proton both of toliprolol and its isomer. In the IR spectra of these two compounds, measured in chloroform, very intense bonded ν(OH stretch) bands were noted and no free ν(OH stretch) bands. The shifts in the ν(OH stretch, υ(NH₂⁺stretch), and υ(NH₂⁺def) bands confirmed the indication from the ¹H NMR data that in the hydrohalide salts of toliprolol and its isomer the halide ion is bonded intramolecularly to both the hydroxyl and ammonium protons. Such an interaction gives rise to a seven-membered ring structure. The assignment of the various bands in the IR spectra was confirmed by measuring the spectra of the compounds with deuterio-exchanged hydroxyl and ammonium groups. The temperature dependence of the resonance frequency of the hydroxyl proton indicated the intramolecular interaction in toliprolol to be somewhat stronger than in its isomer. Although multiplicity changes of the carbon-bound protons of the side to be somewhat stronger than in its isomer. Although multiplicity changes of the carbon-bound protons of the side chains and the absence of any effects of anion variation indicated that, as anticipated, these intramolecular interactins ceased to be present in aqueous medium, the possibility of such an interaction with anionic sites in the hydrophobic microenvironment of the plasma membrane carrying β-adrenoceptors can be imagined. The pharmacological data on toliprolol and its methoxy and chloro derivatives might be interpreted in line with this hypothesis, since replacement of the β-hydroxy group had pronounced negative effects on β-adrenoceptor-blocking activities. However, the low affinity of the isomer and the effects of methoxy and chloro substitution on it indicate additional factors in β-adrenoceptor interaction to be involved as well.