Research article summary (published 23 Jan 2007):

Beta-methyl substitution of cyclohexylalanine in Dmt-Tic-Cha-Phe peptides results in highly potent delta opioid antagonists.

Full 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, beta-MeCha (beta-methyl-cyclohexylalanine). This double substitution led to a new series of opioid peptides displaying subnanomolar delta antagonist activity and mu agonist or antagonist properties depending on the configuration of the beta-MeCha residue. The most promising analog, H-Dmt-Tic-(2S,3S)-beta-MeCha-Phe-OH was a very selective delta antagonist both in the mouse vas deferens (MVD) assay (Ke = 0.241 +/- 0.05 nM) and in radioligand binding assay (K i delta = 0.48 +/- 0.05 nM, K i mu/K i delta = 2800). The epimeric peptide H-Dmt-Tic-(2S,3R)-beta-MeCha-Phe-OH and the corresponding peptide amide turned out to be mixed partial mu agonist/delta antagonists in the guinea pig ileum and MVD assays. Our results constitute further examples of the influence of Dmt and beta-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.

Author information

Author/s: Tóth, Géza (G); Ioja, Eniko (E); Tömböly, Csaba (C); Ballet, Steven (S); Tourwé, Dirk (D); Péter, Antal (A); Martinek, Tamás (T); Chung, Nga N (NN); Schiller, Peter W (PW); Benyhe, Sándor (S); Borsodi, Anna (A);

Affiliation: Institute of Biochemistry, Biological Research Center, Hungarian Academy of Sciences, Post Office Box 521, H-6701 Szeged, Hungary. geza(-atsign-)nucleus.szbk.u-szeged.hu

Journal and publication information

Publication Type: In Vitro; Journal Article; Research Support, Non-U.S. Gov't

Journal: Journal of medicinal chemistry (J Med Chem), published in United States. (Language: eng)

Reference: 2007-Jan; vol 50 (issue 2) : pp 328-33

Dates: Created 2007/01/18; Completed 2007/03/09;

PMID: 17228874, status: MEDLINE (last retrieved date: 2/18/2009)

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

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MeSH headings (categories)

This article was linked to the MeSH Headings (categories) shown below.

Animals Binding, Competitive Brain - metabolism Guinea Pigs Ileum - drug effects; physiology Male Mice Muscle Contraction - drug effects Muscle, Smooth - drug effects; physiology Oligopeptides - chemical synthesis; chemistry; pharmacology

Oligopeptides - chemical synthesis; chemistry; pharmacology Phenylalanine - analogs & derivatives; chemistry Radioligand Assay Rats Rats, Wistar Receptors, Opioid, delta - antagonists & inhibitors Receptors, Opioid, mu - agonists Stereoisomerism Structure-Activity Relationship Vas Deferens - drug effects; physiology

Note: Bold headings indicate primary MeSH headings or qualifiers.

Associated Chemicals: 2',6'-dimethyltyrosyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid-beta-methylcyclohexylalanyl-phenylalanine (0) ; Oligopeptides (0) ; Receptors, Opioid, delta (0) ; Receptors, Opioid, mu (0) ; cyclohexylalanine (4441-50-3) ; Phenylalanine (63-91-2)

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