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

Takashi Yamamoto, Padma Nair, Josef Vagner, Tally Largent-Milnes, Peg Davis, Shou Wu Ma, Edita Navratilova, Sharif Moye, Suneeta Tumati, Josephine Lai, Henry I. Yamamura, Todd W Vanderah, Frank Porreca, Victor J Hruby

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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 δ and μ receptors (Ki = 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 (Ke = 26 nM) and good affinity for the hNK1 receptor (Ki = 14 nM). Consequently, compound 3 is expected to be a promising and novel type of analgesic with bifunctional activities.

Original languageEnglish (US)
Pages (from-to)1369-1376
Number of pages8
JournalJournal of Medicinal Chemistry
Volume51
Issue number5
DOIs
StatePublished - Mar 13 2008

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Neurokinin-1 Receptor Antagonists
Neurokinin-1 Receptors
Peptide Receptors
Opioid Receptors
Structure-Activity Relationship
Substance P
Peptides
Opioid Analgesics
Ileum
Analgesics
Guinea Pigs
Assays
Vas Deferens
Opioid Peptides
Compliance
Bioactivity
Resins
Pharmaceutical Preparations
tyrosyl-alanyl-glycyl-phenylalanine

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

A structure-activity relationship study and combinatorial synthetic approach of C-terminal modified bifunctional peptides that are δ/μ opioid receptor agonists and neurokinin 1 receptor antagonists. / Yamamoto, Takashi; Nair, Padma; Vagner, Josef; Largent-Milnes, Tally; Davis, Peg; Ma, Shou Wu; Navratilova, Edita; Moye, Sharif; Tumati, Suneeta; Lai, Josephine; Yamamura, Henry I.; Vanderah, Todd W; Porreca, Frank; Hruby, Victor J.

In: Journal of Medicinal Chemistry, Vol. 51, No. 5, 13.03.2008, p. 1369-1376.

Research output: Contribution to journalArticle

Yamamoto, Takashi ; Nair, Padma ; Vagner, Josef ; Largent-Milnes, Tally ; Davis, Peg ; Ma, Shou Wu ; Navratilova, Edita ; Moye, Sharif ; Tumati, Suneeta ; Lai, Josephine ; Yamamura, Henry I. ; Vanderah, Todd W ; Porreca, Frank ; Hruby, Victor J. / A structure-activity relationship study and combinatorial synthetic approach of C-terminal modified bifunctional peptides that are δ/μ opioid receptor agonists and neurokinin 1 receptor antagonists. In: Journal of Medicinal Chemistry. 2008 ; Vol. 51, No. 5. pp. 1369-1376.
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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 δ and μ receptors (Ki = 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 (Ke = 26 nM) and good affinity for the hNK1 receptor (Ki = 14 nM). Consequently, compound 3 is expected to be a promising and novel type of analgesic with bifunctional activities.",
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T1 - A structure-activity relationship study and combinatorial synthetic approach of C-terminal modified bifunctional peptides that are δ/μ opioid receptor agonists and neurokinin 1 receptor antagonists

AU - Yamamoto, Takashi

AU - Nair, Padma

AU - Vagner, Josef

AU - Largent-Milnes, Tally

AU - Davis, Peg

AU - Ma, Shou Wu

AU - Navratilova, Edita

AU - Moye, Sharif

AU - Tumati, Suneeta

AU - Lai, Josephine

AU - Yamamura, Henry I.

AU - Vanderah, Todd W

AU - Porreca, Frank

AU - Hruby, Victor J

PY - 2008/3/13

Y1 - 2008/3/13

N2 - 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 δ and μ receptors (Ki = 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 (Ke = 26 nM) and good affinity for the hNK1 receptor (Ki = 14 nM). Consequently, compound 3 is expected to be a promising and novel type of analgesic with bifunctional activities.

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