title: The importance of micelle-bound states for the bioactivities of bifunctional peptide derivatives for delta/mu opioid receptor agonists and neurokinin 1 receptor antagonists.
abstract: To provide new insight into the determining factors of membrane-bound peptide conformation that might play an important role in peptide-receptor docking and further biological behaviors, the dodecylphosphocholine (DPC) micelle-bound conformations of bifunctional peptide derivatives of delta-preferring opioid agonists and NK1 antagonists (1: Tyr-D-Ala-Gly-Phe-Met-Pro-Leu-Trp-O-3,5-Bzl(CF 3) 2; 2: Tyr-D-Ala-Gly-Phe-Met-Pro-Leu-Trp-NH-3,5-Bzl(CF 3) 2; 3: Tyr-D-Ala-Gly-Phe-Met-Pro-Leu-Trp-NH-Bzl) were determined based on 2D NMR studies. Although the differences in the primary sequence were limited to the C-terminus, the obtained NMR conformations were unexpectedly different for each compound. Moreover, their biological activities showed different trends in direct relation to the compound-specific conformations in DPC micelles. The important result is that not only were the NK1 antagonist activities different (the pharmacophore located at the C-terminus)but the opioid agonist activities (this pharmacophore was at the structurally preserved N-terminus) also were shifted, suggesting that a general conformational change in the bioactive state was induced due to relatively small and limited structural modifications.
authors.affiliation: Department of Chemistry, University of Arizona, 1306 East University Boulevard, Tucson, Arizona 85721, USA.
authors.forename: Takashi
authors.initials: T
authors.lastname: Yamamoto
authors.forename: Padma
authors.initials: P
authors.lastname: Nair
authors.forename: Neil E
authors.initials: NE
authors.lastname: Jacobsen
authors.forename: Peg
authors.initials: P
authors.lastname: Davis
authors.forename: Shou-wu
authors.initials: SW
authors.lastname: Ma
authors.forename: Edita
authors.initials: E
authors.lastname: Navratilova
authors.forename: Sharif
authors.initials: S
authors.lastname: Moye
authors.forename: Josephine
authors.initials: J
authors.lastname: Lai
authors.forename: Henry I
authors.initials: HI
authors.lastname: Yamamura
authors.forename: Todd W
authors.initials: TW
authors.lastname: Vanderah
authors.forename: Frank
authors.initials: F
authors.lastname: Porreca
authors.forename: Victor J
authors.initials: VJ
authors.lastname: Hruby
mesh_terms: D000595:Amino Acid Sequence; D045744:Cell Line, Tumor; D006801:Humans; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D008024:Ligands; D008823:Micelles; D008958:Models, Molecular; D064729:Neurokinin-1 Receptor Antagonists; D019906:Nuclear Magnetic Resonance, Biomolecular; D018847:Opioid Peptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D017433:Protein Structure, Secondary; D018040:Receptors, Neurokinin-1 / Q000378:metabolism; D017465:Receptors, Opioid, delta / Q000819:agonists* / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000819:agonists* / Q000378:metabolism; D013050:Spectrometry, Fluorescence
chemical_list: D008024:Ligands; D008823:Micelles; D064729:Neurokinin-1 Receptor Antagonists; D018847:Opioid Peptides; D018040:Receptors, Neurokinin-1; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu