title: Comparison of the conformation of active and nonactive backbone cyclic analogs of substance P as a tool to elucidate features of the bioactive conformation: NMR and molecular dynamics in DMSO and water.
abstract: The conformations of two backbone-cyclized substance P analogs as derived from 1H NMR and molecular dynamics simulations carried out in DMSO and water are described. The method of floating chiralities is used in the simulations to facilitate the diastereotopic assignment of methylene protons. One of the analogs, cyclo-[-(CH2)3-NH-CO-(CH2)4-Arg-Phe-Phe-N-]-CH2-CO-Leu-Met-NH2, is a highly active, selective agonist for the NK-receptor, while the other, cyclo[-(CH2)2-NH-CO-(CH2)2-Gly-Arg-Phe-Phe-N-]-CH2-CO-Leu-Met-NH2, is inactive. Both analogs contain cyclic ring systems of the same size, varying in only the number of amide linkages. From the conformational analysis, the lack of activity can be attributed to the introduction of too much constraint into the ring system. This has an effect on the topological array of the important residues Arg-Phe-Phe. The results presented here are compared with biologically active analogs previously examined. The differences between conformations of active and inactive compounds are used to develop insight into the conformational requirements for biological activity.
authors.affiliation: Institut für Organische Chemie und Biochemie, Technische Universität München, Garching, Germany.
authors.forename: S G
authors.initials: SG
authors.lastname: Grdadolnik
authors.forename: D F
authors.initials: DF
authors.lastname: Mierke
authors.forename: G
authors.initials: G
authors.lastname: Byk
authors.forename: I
authors.initials: I
authors.lastname: Zeltser
authors.forename: C
authors.initials: C
authors.lastname: Gilon
authors.forename: H
authors.initials: H
authors.lastname: Kessler
mesh_terms: D000595:Amino Acid Sequence; D003198:Computer Simulation; D004121:Dimethyl Sulfoxide; D009682:Magnetic Resonance Spectroscopy; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D013329:Structure-Activity Relationship; D013373:Substance P / Q000031:analogs & derivatives / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D013373:Substance P; D004121:Dimethyl Sulfoxide