Arizona Health Sciences

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.

TitleDiscovery 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.
Publication TypeJournal Article
Year of Publication2011
AuthorsYamamoto T, Nair P, Largent-Milnes TM, Jacobsen NE, Davis P, Ma S-W, Yamamura HI, Vanderah TW, Porreca F, Lai J, Hruby VJ
JournalJ Med Chem
Volume54
Issue7
Pagination2029-38
Date Published2011 Apr 14
ISSN1520-4804
KeywordsAmino Acid Sequence, Analgesics, Animals, Drug Discovery, Drug Stability, Guanosine 5'-O-(3-Thiotriphosphate), Guinea Pigs, Humans, Ileum, Magnetic Resonance Spectroscopy, Male, Mice, Micelles, Molecular Conformation, Neurokinin-1 Receptor Antagonists, Peptides, Rats, Receptors, Neurokinin-1, Receptors, Opioid, mu, Receptors, sigma, Structure-Activity Relationship, Tyrosine, Vas Deferens
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.

DOI10.1021/jm101023r
Alternate JournalJ. Med. Chem.
PubMed ID21366266
PubMed Central IDPMC3090346
Grant ListDA-06284 / DA / NIDA NIH HHS / United States
DA-13449 / DA / NIDA NIH HHS / United States
R01 DK017420 / DK / NIDDK NIH HHS / United States
R01 DA013449 / DA / NIDA NIH HHS / United States
P01 DA006284 / DA / NIDA NIH HHS / United States
R01 DK017420-24 / DK / NIDDK NIH HHS / United States
Faculty Member Reference: 
Tally Largent-Milnes, Ph.D.
Frank Porreca, PhD
Todd Vanderah, PhD