Side chain methyl substitution in the δ-opioid receptor antagonist TIPP has an important effect on the activity profile

Dirk Tourwé, Els Mannekens, Trang Nguyen Thi Diem, Patricia Verheyden, Hendrika Jaspers, Géza Töth, A. Péter, Istvân Kertész, Gabriella Török, Nga N. Chung, Peter W. Schiller

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Abstract

The δ-opioid antagonist H-Tyr-Tic-Phe-Phe-OH (TIPP-OH) or its C- terminal amide analogue was systematically modified topologically by substitution of each amino acid residue by all stereoisomers of the corresponding β-methyl amino acid. The potency and selectivity (δ-vs μ- and κ-opioid receptor) were evaluated by radioreceptor binding assays. Agonist or antagonist potency were assayed in the mouse vas deferens and in the guinea pig ileum. In the TIPP analogues containing L-β-methyl amino acids the influence on δ-receptor affinity and on 5-antagonist potency is limited, the [(2S,3R)-β-MePhe3]TIPP-OH analogue being among the most potent 5-antagonists reported. In the D-β-methyl amino acid series, the [D-β- MeTic2] analogues are δ-selective antagonists whereas [D-Tic2]TIPP-NH2 is a δ-agonist. NMR studies did not indicate any influence of the β-methyl substituent on the conformation of the Tic residue. The [(2R,3S)-β- MePhe3]TIPP-NH2 is a potent δ-agonist, its C-terminal carboxylic acid analogue being more δ-selective but displaying partial agonism in both the δ- and μ-bioassay. These results constitute further examples of a profound influence of β-methyl substitution on the potency, selectivity, and signal transduction properties of a peptide.

Original languageEnglish
Pages (from-to)5167-5176
Number of pages10
JournalJournal of Medicinal Chemistry
Volume41
Issue number26
DOIs
Publication statusPublished - Dec 17 1998

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Narcotic Antagonists
Tics
Substitution reactions
Amino Acids
phenylalanylphenylalanine
Radioligand Assay
Stereoisomerism
Vas Deferens
Opioid Receptors
Amino Acid Substitution
Carboxylic Acids
Ileum
Amides
Biological Assay
Signal transduction
Bioassay
Signal Transduction
Guinea Pigs
Conformations
Assays

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Tourwé, D., Mannekens, E., Diem, T. N. T., Verheyden, P., Jaspers, H., Töth, G., ... Schiller, P. W. (1998). Side chain methyl substitution in the δ-opioid receptor antagonist TIPP has an important effect on the activity profile. Journal of Medicinal Chemistry, 41(26), 5167-5176. https://doi.org/10.1021/jm981011u

Side chain methyl substitution in the δ-opioid receptor antagonist TIPP has an important effect on the activity profile. / Tourwé, Dirk; Mannekens, Els; Diem, Trang Nguyen Thi; Verheyden, Patricia; Jaspers, Hendrika; Töth, Géza; Péter, A.; Kertész, Istvân; Török, Gabriella; Chung, Nga N.; Schiller, Peter W.

In: Journal of Medicinal Chemistry, Vol. 41, No. 26, 17.12.1998, p. 5167-5176.

Research output: Contribution to journalArticle

Tourwé, D, Mannekens, E, Diem, TNT, Verheyden, P, Jaspers, H, Töth, G, Péter, A, Kertész, I, Török, G, Chung, NN & Schiller, PW 1998, 'Side chain methyl substitution in the δ-opioid receptor antagonist TIPP has an important effect on the activity profile', Journal of Medicinal Chemistry, vol. 41, no. 26, pp. 5167-5176. https://doi.org/10.1021/jm981011u
Tourwé, Dirk ; Mannekens, Els ; Diem, Trang Nguyen Thi ; Verheyden, Patricia ; Jaspers, Hendrika ; Töth, Géza ; Péter, A. ; Kertész, Istvân ; Török, Gabriella ; Chung, Nga N. ; Schiller, Peter W. / Side chain methyl substitution in the δ-opioid receptor antagonist TIPP has an important effect on the activity profile. In: Journal of Medicinal Chemistry. 1998 ; Vol. 41, No. 26. pp. 5167-5176.
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AU - Jaspers, Hendrika

AU - Töth, Géza

AU - Péter, A.

AU - Kertész, Istvân

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AU - Chung, Nga N.

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