Arizona Health Sciences

A structure-activity relationship study and combinatorial synthetic approach of C-terminal modified bifunctional peptides that are delta/mu opioid receptor agonists and neurokinin 1 receptor antagonists.

TitleA structure-activity relationship study and combinatorial synthetic approach of C-terminal modified bifunctional peptides that are delta/mu opioid receptor agonists and neurokinin 1 receptor antagonists.
Publication TypeJournal Article
Year of Publication2008
AuthorsYamamoto T, Nair P, Vagner J, Largent-Milnes T, Davis P, Ma S-W, Navratilova E, Moye S, Tumati S, Lai J, Yamamura HI, Vanderah TW, Porreca F, Hruby VJ
JournalJ Med Chem
Volume51
Issue5
Pagination1369-76
Date Published2008 Mar 13
ISSN0022-2623
KeywordsAnimals, Cell Line, Cell Line, Tumor, Combinatorial Chemistry Techniques, Cricetinae, Cricetulus, Electric Stimulation, Guinea Pigs, Humans, Ileum, In Vitro Techniques, Male, Mice, Muscle Contraction, Muscle, Smooth, Neurokinin-1 Receptor Antagonists, Oligopeptides, Radioligand Assay, Rats, Receptors, Opioid, delta, Receptors, Opioid, mu, Structure-Activity Relationship, Vas Deferens
Abstract

A series of bifunctional peptides with opioid agonist and substance P antagonist bioactivities were designed with the concept of overlapping pharmacophores. In this concept, the bifunctional peptides were expected to interact with each receptor separately in the spinal dorsal horn where both the opioid receptors and the NK1 receptors were found to be expressed, to show an enhanced analgesic effect, no opioid-induced tolerance, and to provide better compliance than coadministration of two drugs. Compounds were synthesized using a two-step combinatorial method for C-terminal modification. In the method, the protected C-terminal-free carboxyl peptide, Boc-Tyr( tBu)- d-Ala-Gly Phe-Pro-Leu-Trp(Boc)-OH, was synthesized as a shared intermediate using Fmoc solid phase chemistry on a 2-chlorotrityl resin. This intermediate was esterified or amidated in solution phase. The structure-activity relationships (SAR) showed that the C-terminus acted as not only a critical pharmacophore for the substance P antagonist activities, but as an address region for the opioid agonist pharmacophore that is structurally distant from the C-terminal. Among the peptides, H-Tyr- d -Ala-Gly-Phe-Pro-Leu-Trp-NH-Bzl ( 3) demonstrated high binding affinities at both delta and mu receptors ( K i = 10 and 0.65 nM, respectively) with efficient agonist functional activity in the mouse isolated vas deferens (MVD) and guinea pig isolated ileum (GPI) assays (IC 50 = 50 and 13 nM, respectively). Compound 3 also showed a good antagonist activity in the GPI assay with substance P stimulation ( K e = 26 nM) and good affinity for the hNK1 receptor ( K i = 14 nM). Consequently, compound 3 is expected to be a promising and novel type of analgesic with bifunctional activities.

DOI10.1021/jm070332f
Alternate JournalJ. Med. Chem.
PubMed ID18266313
PubMed Central IDPMC2737825
Grant ListDA-06284 / DA / NIDA NIH HHS / United States
P01 DA006284-18A1 / DA / NIDA NIH HHS / United States
DA-13449 / DA / NIDA NIH HHS / United States
R01 DA013449 / DA / NIDA NIH HHS / United States
P01 DA006284 / DA / NIDA NIH HHS / United States
R01 DA013449-09 / DA / NIDA NIH HHS / United States
Faculty Member Reference: 
Tally Largent-Milnes, Ph.D.
Edita Navratilova, Ph.D.
Frank Porreca, PhD
Todd Vanderah, PhD