title: Discovery of a potent and efficacious peptide derivative for δ/μ opioid agonist/neurokinin 1 antagonist activity with a 2',6'-dimethyl-L-tyrosine: in vitro, in vivo, and NMR-based structural studies.
abstract: Multivalent ligands with δ/μ opioid agonist and NK1 antagonist activities have shown promising analgesic potency without detectable sign of toxicities, including motor skill impairment and opioid-induced tolerance. To improve their biological activities and metabolic stability, structural optimization was performed on our peptide-derived lead compounds by introducing 2',6'-dimethyl-L-tyrosine (Dmt) instead of Tyr at the first position. The compound 7 (Dmt-D-Ala-Gly-Phe-Met-Pro-Leu-Trp-NH-[3',5'-(CF(3))(2)-Bzl]) showed improved multivalent bioactivities compared to those of the lead compounds, had more than 6 h half-life in rat plasma, and had significant antinociceptive efficacy in vivo. The NMR structural analysis suggested that Dmt(1) incorporation in compound 7 induces the structured conformation in the opioid pharmacophore (N-terminus) and simultaneously shifts the orientation of the NK1 pharmacophore (C-terminus), consistent with its affinities and activities at both opioid and NK1 receptors. These results indicate that compound 7 is a valuable research tool to seek a novel analgesic drug.
authors.affiliation: Department of Chemistry and Biochemistry, University of Arizona, 1306 East University Boulevard, Tucson, Arizona 85721, United States.
authors.forename: Takashi
authors.initials: T
authors.lastname: Yamamoto
authors.forename: Padma
authors.initials: P
authors.lastname: Nair
authors.forename: Tally M
authors.initials: TM
authors.lastname: Largent-Milnes
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: 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: Josephine
authors.initials: J
authors.lastname: Lai
authors.forename: Victor J
authors.initials: VJ
authors.lastname: Hruby
mesh_terms: D000595:Amino Acid Sequence; D000700:Analgesics / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D055808:Drug Discovery; D004355:Drug Stability; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006168:Guinea Pigs; D006801:Humans; D007082:Ileum / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D008823:Micelles; D008968:Molecular Conformation; D064729:Neurokinin-1 Receptor Antagonists; D010455:Peptides / Q000737:chemistry*; D051381:Rats; D018040:Receptors, Neurokinin-1 / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000819:agonists* / Q000378:metabolism; D017480:Receptors, sigma / Q000819:agonists* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D014649:Vas Deferens / Q000378:metabolism
chemical_list: D000700:Analgesics; D008823:Micelles; D064729:Neurokinin-1 Receptor Antagonists; D010455:Peptides; D018040:Receptors, Neurokinin-1; D017450:Receptors, Opioid, mu; D017480:Receptors, sigma; C076121:2',6'-dimethyltyrosine; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D014443:Tyrosine