title: High resolution NMR conformational studies of new bivalent NOP receptor antagonists in model membrane systems.
abstract: 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.
authors.affiliation: Istituto Superiore di Sanità, Dipartimento del Farmaco, Viale Regina Elena 299, Rome, Italy. anna.borioni@iss.it
authors.forename: Anna
authors.initials: A
authors.lastname: Borioni
authors.forename: Giuditta
authors.initials: G
authors.lastname: Bastanzio
authors.forename: Maurizio
authors.initials: M
authors.lastname: Delfini
authors.forename: Carlo
authors.initials: C
authors.lastname: Mustazza
authors.forename: Fabio
authors.initials: F
authors.lastname: Sciubba
authors.forename: Massimo
authors.initials: M
authors.lastname: Tatti
authors.forename: Maria Rosaria
authors.initials: MR
authors.lastname: Del Giudice
mesh_terms: D002784:Cholesterol / Q000737:chemistry; D004134:Dimyristoylphosphatidylcholine / Q000737:chemistry; D006801:Humans; D008024:Ligands; D008051:Lipid Bilayers / Q000737:chemistry*; D008081:Liposomes / Q000737:chemistry; D008823:Micelles; D008958:Models, Molecular; D009292:Narcotic Antagonists / Q000737:chemistry* / Q000494:pharmacology*; D019906:Nuclear Magnetic Resonance, Biomolecular; D010713:Phosphatidylcholines / Q000737:chemistry; D011804:Quinolines / Q000737:chemistry* / Q000494:pharmacology*; D011957:Receptors, Opioid / Q000378:metabolism; D000094942:Nociceptin Receptor
chemical_list: D008024:Ligands; D008051:Lipid Bilayers; D008081:Liposomes; D008823:Micelles; D009292:Narcotic Antagonists; D010713:Phosphatidylcholines; D011804:Quinolines; D011957:Receptors, Opioid; D002784:Cholesterol; D004134:Dimyristoylphosphatidylcholine; D000094942:Nociceptin Receptor; C000722283:OPRL1 protein, human