High resolution NMR conformational studies of new bivalent NOP receptor antagonists in model membrane systems

• Published in: Bioorganic chemistry 2011-02, Vol.39 (1), p.59-66
• Main Authors: Borioni, Anna, Bastanzio, Giuditta, Delfini, Maurizio, Mustazza, Carlo, Sciubba, Fabio, Tatti, Massimo, Giudice, Maria Rosaria Del
• Format: Article
• Language: English
• Subjects: Cholesterol - chemistry; Dimyristoylphosphatidylcholine - chemistry; Humans; Ligands; Lipid Bilayers - chemistry; Liposomes; Liposomes - chemistry; Micelles; Models, Molecular; Narcotic Antagonists - chemistry; Narcotic Antagonists - pharmacology; NMR; Nuclear Magnetic Resonance, Biomolecular; Opioid antagonists; Phosphatidylcholines - chemistry; Quinoline derivatives; Quinolines - chemistry; Quinolines - pharmacology; Receptors, Opioid - metabolism
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2010.12.001

A proton NMR investigation on the behaviour of a bivalent quinolinic ligand of the NOP receptor in the presence of cell membrane models showed a conformational change of the molecule caused by the interaction. [Display omitted] ► Bivalent antagonists of the Nociceptin receptor. ► 2D NMR study of the molecules in interaction with membrane models. ► Determination of conformational features of the molecules on the basis of NMR data. The interaction of new bivalent NOP receptor antagonists with dodecyl phosphatidylcholine micelles and DMPC/cholesterol liposomes was investigated in solution by high resolution NMR. The ligands are structurally related to the NOP antagonist JTC-801 plus a propanediamine or heptanediamine spacer between the pharmacophoric units . Ligand internuclear distances were derived from 2D NOESY data and applied to molecular modelling calculations as conformational restraints. NMR experiments on micelles evidenced that the ligands closely approached the micelles but gave no hints on the preferential conformations of the interacting ligands. Results from NMR experiments in the presence of liposomes clearly indicated that both ligands strongly interacted with the bilayer assuming a preferential folded conformation with the quinoline arms superimposing on each other. The finding suggested that these strongly lipophilic pharmacophores could localize in the native receptorial membrane in the form of a depot, gaining access to the recognition site via the lipid bilayer.