β-methyl substitution of cyclohexylalanine in Dmt-Tic-Cha-Phe peptides results in highly potent δ opioid antagonists

Géza Tóth, Eniko Ioja, C. Tömböly, Steven Ballet, Dirk Tourwé, A. Péter, T. Martinek, Nga N. Chung, Peter W. Schiller, S. Benyhe, A. Borsodi

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

The opioid peptide TIPP (H-Tyr-Tic-Phe-Phe-OH, Tic: 1,2,3,4- tetrahydroisoquinoline-3-carboxylic acid) was substituted with Dmt (2′,6′-dimethyltyrosine) and a new unnatural amino acid, β-MeCha (β-methylcyclohexylalanine). This double substitution led to a new series of opioid peptides displaying subnanomolar δ antagonist activity and μ agonist or antagonist properties depending on the configuration of the β-MeCha residue. The most promising analog, H-Dmt-Tic-(2S,3S)-β-MeCha-Phe-OH was a very selective δ antagonist both in the mouse vas deferens (MVD) assay (Ke = 0.241 ± 0.05 nM) and in radioligand binding assay (Kiδ = 0.48 ± 0.05 nM, Kiμ/Kiδ = 2800). The epimeric peptide H-Dmt-Tic-(2S,3R)-β-MeCha-Phe-OH and the corresponding peptide amide turned out to be mixed partial μ agonist/δ antagonists in the guinea pig ileum and MVD assays. Our results constitute further examples of the influence of Dmt and β-methyl substitution as well as C-terminal amidation on the potency, selectivity, and signal transduction properties of TIPP related peptides. Some of these compounds represent valuable pharmacological tools for opioid research.

Original languageEnglish
Pages (from-to)328-333
Number of pages6
JournalJournal of Medicinal Chemistry
Volume50
Issue number2
DOIs
Publication statusPublished - Jan 25 2007

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Tics
Narcotic Antagonists
Assays
Substitution reactions
Vas Deferens
Opioid Peptides
Peptides
Signal transduction
Radioligand Assay
Ileum
Amides
Opioid Analgesics
Signal Transduction
Guinea Pigs
Pharmacology
Amino Acids
Research
cyclohexylalanine
tyrosyl-1,2,3,4-tetrahydro-3-isoquinolinecarbonyl-phenylalanyl-phenylalanine

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

β-methyl substitution of cyclohexylalanine in Dmt-Tic-Cha-Phe peptides results in highly potent δ opioid antagonists. / Tóth, Géza; Ioja, Eniko; Tömböly, C.; Ballet, Steven; Tourwé, Dirk; Péter, A.; Martinek, T.; Chung, Nga N.; Schiller, Peter W.; Benyhe, S.; Borsodi, A.

In: Journal of Medicinal Chemistry, Vol. 50, No. 2, 25.01.2007, p. 328-333.

Research output: Contribution to journalArticle

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abstract = "The opioid peptide TIPP (H-Tyr-Tic-Phe-Phe-OH, Tic: 1,2,3,4- tetrahydroisoquinoline-3-carboxylic acid) was substituted with Dmt (2′,6′-dimethyltyrosine) and a new unnatural amino acid, β-MeCha (β-methylcyclohexylalanine). This double substitution led to a new series of opioid peptides displaying subnanomolar δ antagonist activity and μ agonist or antagonist properties depending on the configuration of the β-MeCha residue. The most promising analog, H-Dmt-Tic-(2S,3S)-β-MeCha-Phe-OH was a very selective δ antagonist both in the mouse vas deferens (MVD) assay (Ke = 0.241 ± 0.05 nM) and in radioligand binding assay (Kiδ = 0.48 ± 0.05 nM, Kiμ/Kiδ = 2800). The epimeric peptide H-Dmt-Tic-(2S,3R)-β-MeCha-Phe-OH and the corresponding peptide amide turned out to be mixed partial μ agonist/δ antagonists in the guinea pig ileum and MVD assays. Our results constitute further examples of the influence of Dmt and β-methyl substitution as well as C-terminal amidation on the potency, selectivity, and signal transduction properties of TIPP related peptides. Some of these compounds represent valuable pharmacological tools for opioid research.",
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AU - Ballet, Steven

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AU - Péter, A.

AU - Martinek, T.

AU - Chung, Nga N.

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